The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index; 1 of the 11 sources its claims cite were checked for support.
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial
Open accessAbstract
Importance Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. Objective To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant. Design, Setting, and Participants In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase. Interventions Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. Main Outcomes and Measures Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test. Results Among the 297 adults (mean age [SD]…
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
36 Own result · 15 Own method · 6 No full text of the sources · 6 Own interpretation · 2 Sources not found · 2 No basis given · 1 Partly supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Results were consistent with previous findings from completed short-term (4-week) phase 2 and 3 studies.10,12,15”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Discussion
What the sources say
- Partly supportedcites [10] 10. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: results of a double-blind, doubly-randomized, placebo-controlled study. JAMA Psychiatry. 2018;75(2):139-148. doi:10.1001/ jamapsychiatry.2017.3739 sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) says the esketamine doses appeared safe, with no new or unexpected safety concerns. But the Design describes this as a phase 2 study with two one-week double-blind periods; the paper does not compare its safety results with completed four-week phase 2 and 3 studies. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [12] 12. Popova V, Daly E, Trivedi M, et al. Randomized, double-blind study of flexibly-dosed intranasal esketamine plus oral antidepressant vs active control in treatment-resistant depression. Paper presented at: 2018 American Society for Clinical Pathology Annual Meeting; May 30, 2018; source
- Not checked — no full text of the sourcecites [15] 15. Fedgchin M, Trivedi M, Daly EJ, et al. Randomized, double-blind study of fixed-dose intranasal esketamine plus oral antidepressant vs. active control in treatment-resistant depression (abstract 18). Presented at the 9th Biennial Conference of the International Society for Affective Disorders (ISAD) and the Houston Mood Disorders Conference; September 21, 2018; source
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
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
“No clinically significant change in electrocardiographic findings was observed during the study.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
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 HRs were 0.49 (95% CI, 0.27-0.90)for direct-entry patients and 0.45 (95% CI, 0.17-1.18)for transfer-entry patients.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Efficacy Results
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.
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
“Overall, among patients who achieved stable remission, 24 patients (26.7%) in the esketamine and antidepressant group and 39 patients (45.3%) in the antidepressant and placebo group experienced a relapse event during the maintenance phase”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Efficacy Results
plainn = 24- 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, in a post hoc analysis, esketamine and antidepressant delayed relapse compared with antidepressant and placebo among patients who achieved stable remission and patients who achieved stable response combined (HR, 0.38; 95% CI, 0.26-0.57;P < .001).”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Efficacy Results
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.
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
“On the basis of the C-SSRS, there were no reports of suicidal behavior in the optimization or maintenance phases.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
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
“Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Abstract
plainn = 297- 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
“None of the patients who experienced relapse had a significant elevation in C-SSRS score (ie, the most severe postbaseline score was 2 for patients who experienced relapse in the esketamine and antidepressant group and 3 for patients who experienced relapse in the antidepressant and placebo group).”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
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
“No serious AEs considered as related to esketamine were reported during the optimization or maintenance phases.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
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 HRs were 0.49 (95% CI, 0.27-0.90)for direct-entry patients and 0.45 (95% CI, 0.17-1.18)for transfer-entry patients.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Efficacy Results
plaincorrelational- 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. 21
- Probably not a substantial claim. 19
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
“Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84)among patients who achieved stable remission”
- Also stated in: § Efficacy Results · plain
“Continued treatment with esketamine and antidepressant significantly delayed relapse compared with treatment with antidepressant and placebo (patients who achieved stable remission: HR, 0.49; 95% CI, 0.29-0.84;P = .003,number needed to treat [NNT], 6;”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Abstract
plaindirectn = 24- 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.
- Also stated in: § Efficacy Results · 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
“No cases of respiratory depression or interstitial cystitis were observed.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
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 most common adverse events reported for esketamine-treated patients after randomization weretransientdysgeusia,vertigo,dissociation,somnolence,anddizziness(incidence,20.4%-27.0%),each reported in fewer patients (<7%) treated with an antidepressant and placebo.”
- Also stated in: § Safety Results · plain
“The 5 most common AEs reported in the esketamine and antidepressant group during the maintenance phase were dysgeusia, vertigo, dissociation, somnolence, and dizziness (Table 3).”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Abstract
plainn = 297- 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: § Safety Results · 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
“Seven patients experienced 1 or more AEs during the maintenance phase, leading to discontinuation of the intranasal study drug; 4 (2.6%) of 152 were in the esketamine and antidepressant group (worsening depression, 3 patients; anxiety and confusional state [transient], 1 patient) and 3 (2.1%) of 145 were in the antidepressant and placebo group (worsening depression for each).”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
plainn = 7- 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
“Continued treatment with esketamine and antidepressant significantly delayed relapse compared with treatment with antidepressant and placebo (patients who achieved stable remission: HR, 0.49; 95% CI, 0.29-0.84;P = .003,number needed to treat [NNT], 6; patients who achieved stable response: HR, 0.30; 95% CI, 0.16-0.55:P < .001,NNT, 4).”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Efficacy Results
plaindirectn = 16 ·- 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
“On the basis of this analysis, the HR was estimated to range from 0.42 to 0.57, which is consistent with the overall HR of 0.47 (unweighted).”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Efficacy Results
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.
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 those patients treated with esketamine and oral antidepressant who reported no suicidal ideation or behavior at baseline, 42 (11.6%)had a higher postbaseline score (maximum C-SSRS score of 1 ) in the optimization phase; and 3 (2.4%) had a higher postbaseline score (maximum C-SSRS score of 1 [n = 2] and 4 [n = 1]) compared with 6 patients (4.5%) receiving antidepressant and placebo (maximum C-SS”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
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
“Few patients experienced treatment-emergent transient hypertension, defined 0 100 80 Patients Without Relapse, % 60 40 20 0 100 80 Patients Without Relapse, % 60 40 20 B Patients who achieved stable response No. at risk Esketamine nasal spray and oral antidepressant Oral antidepressant and placebo nasal spray 0 90 86 84 69 74 52 58 41 53 34 39 28 31 22 25 19 20 12 14 10 10 7 8 4 7 3 7 3 6 3 5 3 2”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
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 direct-entry patients (362 [85.4%]) had baseline C-SSRS scores of 0, indicating no suicidal ideation or behavior.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
plain- 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
“After completing induction and optimization treatment (16 weeks total), in patients who achieved stable remission and those who achieved stable response, there was separation in MADRS total scores between patients randomized to continue vs discontinue esketamine treatment, each in the presence of antidepressant therapy, with MADRS total scores being lower over time for esketamine-treated patients.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Efficacy Results
plaincorrelational- 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
“Nineteen of the 39 relapses in patients who achieved stable remission and who were switched to placebo nasal spray occurred in the first month after discontinuation of esketamine treatment (6 by week 2 and the remainder by week 4), with 11 of these 19 early relapses occurring in patients who had required weekly treatment administration in the last 4 weeks of the optimization phase before randomiz”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Efficacy Results
plainn = 39- 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
“No deaths were reported during the study.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
plain- 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
“Most AEs were mild to moderate, observed after dosing, and generally resolved in the same day.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
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
“Transient blood pressure increases were observed with esketamine on treatment days; the maximum value was reached at 40 minutes after the start of administration in most cases and typically returned to the predose range by 1.5 hours after administration”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
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. 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 symptoms or AEs of psychosis were observed.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
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
“Present-state dissociative symptoms, as measured by CADSS (eFigure 4 in Supplement 2), began shortly after the start of esketamine treatment, peaked at 40 minutes, and generally resolved by 1.5 hours.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
plain- 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
“Present-state dissociative symptoms, as measured by CADSS (eFigure 4 in Supplement 2), began shortly after the start of esketamine treatment, peaked at 40 minutes, and generally resolved by 1.5 hours.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
plain- 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.
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
“Randomization was balanced using randomly permuted blocks and stratified by country.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Maintenance Phase
plain- 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.
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
“Patients who achieved stable remission and those who achieved stable response (without remission) were separately randomized 1:1 according to a computer-generated schedule to continue esketamine treatment or discontinue esketamine treatment and switch to placebo nasal spray, each in addition to oral antidepressant treatment.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Maintenance Phase
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.
Probably not a substantial claim.
In the paper
“Even when patients with TRD respond to treatment, the overall relapse rate while continuing treatment with the same antidepressant is high after 2 (65%; within 3.1 months) and 3 failed trials (71.1%; within 3.3 months).3”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > D
What the sources say
- Not checked — no full text of the sourcecites [3] 3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163 (11):1905-1917. doi:10.1176/ajp.2006.163.11.1905 source
plaincorrelational- 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
“Because patients with treatment resistance who achieve remission reportedly have lower relapse rates compared with those who respond but do not experience remission, 3 the prespecified primary analysis was conducted using the analysis of patients who achieved stable remission.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Maintenance Phase
What the sources say
- Not checked — no full text of the sourcecites [3] 3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163 (11):1905-1917. doi:10.1176/ajp.2006.163.11.1905 source
hedgedcorrelational- 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
“One patient who did not meet stable remission or stable response criteria at the end of the optimization phase was incorrectly randomized in the group with stable response.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Conclusions
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.
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 placebo solution contained a bittering agent (denatonium benzoate) to simulate the taste of esketamine solution and maintain the blinding.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Intranasal Study Drug and Administration
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.
In the paper
“The study was conducted in accordance with ethical principles of the Declaration of Helsinki, 16 Good Clinical Practices, and applicable regulatory requirements.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Study Population
What the sources say
- Not matchedcites [16] 16. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi:10. 1001/jama.2013.281053
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- 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.
- Not matched
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
“A 2-stage group-sequential design was implemented for the analysis set of patients who achieved stable remission, and an independent data-monitoring committee performed a prespecified interim analysis after 31 relapses to assess early efficacy.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Sample Size Determination
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.
Probably not a substantial claim. It may state two separate claims as one.
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
“Study limitations include the fact that esketamine has known transient dissociative and sedative effects that are difficult to blind; these symptoms could have biased the staff who observed treatment administration.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Discussion
hedgedconditional- 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.
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
“Institutional review boards and independent ethics committees (eAppendix 1 in Supplement 2) approved the study protocol and amendments.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Study Population
plain- 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.
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
“Independent, blinded, remote raters performed MADRS assessments throughout the study (weeks 1, 2, and 4 of the screening and observation phase and weekly during the induction, optimization, maintenance, and follow-up phases).”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Efficacy Assessments
plain- 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.
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
“On the basis of assumptions (accrual period and rate, maximum study duration, and dropout rate), 211 patients who achieved stable remission needed to be randomized (1:1 ratio) to obtain 84 relapses, providing 90% power to detect a hazard ratio (HR) of 0.49 at a 2-sided α of .05 for a fixed-sample design to detect superiority of esketamine and antidepressant over antidepressant and placebo in delay”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Sample Size Determination
plainn = 211- 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.
In the paper
“The interim analysis on patients who achieved stable remission did not show superiority of esketamine and antidepressant over antidepressant and placebo (at a 2-sided significance level of .0097,log-rank test); therefore, the study continued, and the number of relapses in patients who achieved stable remission was reestimated to 59 relapses in total with an adjusted significance level of .046(2-s”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Sample Size Determination
What the sources say
- Not checked — no full text of the sourcecites [24] 24. Wang SK, Tsiatis AA. Approximately optimal one-parameter boundaries for group sequential trials. Biometrics. 1987;43(1):193-199. doi:10.2307/ 2531959 source
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.
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
“Most censored patients (ie, when participation was ended) were considered as administrative based on the study having reached its end point (ie, based on the target number of relapse events having been achieved and the study stopping).Only 13 (8 patients who achieved stable remission and 5 patients who achieved stable response) in the esketamine nasal spray and oral antidepressant group and 12 (9”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Efficacy Results
plainn = 5- 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.
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
“All patients provided written informed consent before entering the study.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Study Population
plain- 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.
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
“One patient who achieved stable response was incorrectly randomized as a patient who achieved stable remission at the end of the optimization phase.One patient did not meet stable remission or stable response criteria and was incorrectly randomized as a patient with stable response.”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Safety Results
plain- 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.
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
“or another clinically relevant event suggestive of relapse (assessed by a relapse adjudication committee).”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Efficacy End Points and Analyses
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.
Probably not a substantial claim.
The paper relies on this without support.
Little is known about maintaining antidepressant effects of esketamine and ketamine in the long term.
“In contrast to available data about short-term antidepressant effects of esketamine and ketamine, 13,14 little is known about maintaining antidepressant effects in the long term.”
The paper relies on this without support.
This is the first controlled maintenance study of esketamine.
“We report the findings of, to our knowledge, the first controlled maintenance study of esketamine that evaluated whether continued use of intermittently administered esketamine nasal spray plus an oral antidepressant can sustain antidepressant effects among patients with TRD to a greater extent than an oral antidepressant alone.”
The paper relies on this without support.
There is a substantial unmet need for effective treatments that can sustain antidepressant benefits for the population with treatment-resistant depression.
“There is a substantial unmet need for effective treatments that can sustain antidepressant benefits for the population with TRD.”
The paper relies on this without support.
Esketamine plasma concentrations decrease rapidly for the initial 2 to 4 hours and more gradually thereafter, with a mean terminal half-life of 7-12 hours, and steady state is never reached with intermittent dosing.
“the decrease in esketamine plasma concentrations is rapid for the initial 2 to 4 hours and more gradual thereafter (mean terminal half-life, 7-12 hours), with steady state never reached with intermittent dosing.”
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
“A follow-up report observed that prolonged treatment (weekly or biweekly treatment) with (S)-ketamine nasal spray (56-84 mg; 16 weeks), in conjunction with an oral antidepressant (SSRI or a selective norepinephrine reuptake inhibitor [SNRI]), was well-tolerated with significant remission of symptoms.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Daly et al., 2019
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
“With regard to esketamine in particular, clinical use was largely based on four positive Phase 3 efficacy studies [62][63][64][65] that informed the subsequent FDA approval of intranasal esketamine for TRD and suicidal ideation with intent, as described above.”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [62]
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
“Induction trials largely ended at 4 weeks, while maintenance trials relied on designs that include enrichment (randomized withdrawal of responders/remitters) (22)”
From Intranasal esketamine plus oral antidepressant for treatment-resistant depression: acute induction and maintenance relapse-prevention outcomes in a systematic review and meta-analysis (2026) · cites this paper as [22]
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
“In the continuation trial (NCT02493868 [12]), the primary outcome of remission remained consistent except when data from all Polish centers were excluded; in this case, the effect size decreased and the analysis was not statistically significant.”
From Efficacy and safety of esketamine for “treatment resistant depression”: registered report for a systematic review with an individual patient data meta-analysis of randomized, double-blind, placebo-controlled trials (2025) · cites this paper as [12]
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
“Across clinical trials, ketamine and esketamine reliably produce rapid symptom relief, yet responses frequently decay within days to weeks, with high relapse rates following discontinuation [81,82,83].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [83]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“Further, patients who were in remission were more likely to relapse when switched to a placebo nasal spray in conjunction with an oral antidepressant”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Daly et al., 2019
The cited source says what the claim attributes to it.
In the citing paper
“Maintenance regimens extend benefit for some patients but only partially offset this erosion [82,83,84].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [83]
The cited source says what the claim attributes to it.
In the citing paper
“randomized-withdrawal designs answer a relapse-prevention question in an enriched population, not an initiation question in an unselected TRD population (22)”
The cited source says what the claim attributes to it.
In the citing paper
“Our findings are concordant with the direction and general magnitude of effect reported in pivotal trials of adjunctive intranasal esketamine in TRD and the relapse-prevention study (18–23)”
In the citing paper
“Two maintenance studies followed patients on maintenance esketamine up to 88 weeks, and reported decreased risk of depressive relapse when patients used esketamine weekly or every second week,74 and provided reassuring data on safety to over 1 year of esketamine use.75”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [74]
In the citing paper
“However, when reviewing the major esketamine trials, significantly increased rates of somnolence versus placebo have been reported, especially in relapse-prevention studies,74,152 but this has not been seen consistently.153”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [74]
In the citing paper
“Repeated dosing of ketamine is more efficacious in clinical trials than typical antidepressants alone [109, 110].”
From Beyond the serotonin deficit hypothesis: Communicating a neuroplasticity framework of major depressive disorder (2024) · cites this paper as [109]
In the citing paper
“A recent, longer (4 months) clinical trial by Daly and colleagues demonstrated a significant dose–response curve associated with esketamine augmentation [112].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [112]
In the citing paper
“Findings regarding both safety and efficacy in the trial are of limited applicability due to a high dropout rate [112].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [112]
In the citing paper
“Long-term esketamine use in Daly and colleagues’ study was also linked to short-term, adverse effects, including increases in blood pressure, dissociative experiences, and incidents of worsening depression when compared with placebo.”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [112]
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 interim efficacy results from SUSTAIN-3 are consistent with the results of a trial testing the maintenance efficacy of esketamine plus oral antidepressant using a randomized withdrawal design [10].”
In the citing paper
“Although 'treatment-resistant depression' sounds rare and severe, Janssen's definition, consisting of people who have 'failed' two different antidepressants, is likely to encompass many current antidepressant users.17”
From Are we repeating mistakes of the past? A review of the evidence for esketamine (2021) · cites this paper as [17]
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 minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Maintenance Phase
“At week 16 of the optimization phase, esketamine-treated direct-entry (open-label treatment) and transfer-entry patients (double-blind treatment) who had achieved stable remission”
§ Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression A Randomized Clinical Trial > Transfer-Entry and Direct-Entry Patients
“entered a 12-week optimization phase”
Citations
Cites
Diagnostic and Statistical Manual of Mental Disorders
American Psychiatric Association (2013) · doi:10.1176/appi.books.9780890425596 · Cited by 116,369
The Brief Psychiatric Rating Scale.
Overall, J. E., & Gorham, D. R. (1962) · Psychological Reports · doi:10.2466/pr0.1962.10.3.799 · Cited by 11,090
Diagnostic and Statistical Manual of Mental Disorders(DSM)
Leong, F. T. L. (2008) · Sage eBooks · doi:10.4135/9781412963978.n182 · Cited by 10,861
Cook, R. J., Dickens, B. M., & Fathalla, M. F. (2003) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780199241323.003.0025 · Cited by 10,825
Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., Niederehe, G., Thase, M. E., Lavori, P. W., Lebowitz, B. D., et al. (2006) · American Journal of Psychiatry · doi:10.1176/ajp.2006.163.11.1905 · Cited by 5,643 · cited 1×
“The study consisted of up to 5 phases: (1) a 4-week screening and prospective observation phase (direct-entry patients only); (2) a 4-week open-label induction phase (direct-entry patients only); (3) a 12-week optimization phase (open-label, directentry patients or double-blind, transfer-entry patients); (4) a mainten…”
MethodSelf-citationA randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766
Self-citationWalker, E. R., McGee, R. E., & Druss, B. G. (2015) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2014.2502 · Cited by 2,976
Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, A. M., Iqbal, S., Pillemer, S., Foulkes, A., Shah, A., et al. (2013) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2013.13030392 · Cited by 1,205
Posner, K., Oquendo, M. A., Gould, M., Stanley, B., & Davies, M. (2007) · American Journal of Psychiatry · doi:10.1176/ajp.2007.164.7.1035 · Cited by 1,025
Cited by
Sorted by citations
McIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., Sanacora, G., Murrough, J. W., Berk, M., Brietzke, E., Dodd, S., Gorwood, P., Ho, R., et al. (2021) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2020.20081251 · Cited by 731
“Intranasal esketamine combined with a conventional antidepressant decreased the risk of relapse by 51% among personswhohad achieved stable remission and 70% among those who achieved a stable responsewithacute therapy (60).”
BackgroundSelf-citationMalhi, G. S., Bell, E., Bassett, D., Boyce, P., Bryant, R., Hazell, P., Hopwood, M., Lyndon, B., Mulder, R., Porter, R., et al. (2021) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/0004867420979353 · Cited by 614
“A placebo-controlled relapse prevention trial has also demonstrated prevention of depressive relapse after acute treatment (Daly et al., 2019).”
BackgroundFedgchin, M., Trivedi, M., Daly, E. J., Melkote, R., Lane, R., Lim, P., Vitagliano, D., Blier, P., Fava, M., Liebowitz, M., et al. (2019) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyz039 · Cited by 606
Self-citationNovel and emerging treatments for major depression
Marwaha, S., Palmer, E. R., Suppes, T. M., Cons, E., Young, A. H., & Upthegrove, R. (2022) · The Lancet · doi:10.1016/s0140-6736(22)02080-3 · Cited by 618
García-Gutiérrez, M. S., Navarrete, F., Gasparyan, A., Austrich-Olivares, A., Sala, F., & Manzanares, J. (2020) · Biomolecules · doi:10.3390/biom10111575 · Cited by 306
Wajs, E., Aluisio, L., Holder, R., Daly, E. J., Lane, R., Lim, P., George, J. E., Morrison, R. L., Sanacora, G., Young, A. H., et al. (2020) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.19m12891 · Cited by 308
Self-citationMcAllister-Williams, R. H., Arango, C., Blier, P., Demyttenaere, K., Falkai, P., Gorwood, P., Hopwood, M., Javed, A., Kasper, S., Malhi, G. S., et al. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.02.023 · Cited by 278
Self-citationKetamine and rapid antidepressant action: New treatments and novel synaptic signaling mechanisms
Krystal, J. H., Kavalali, E. T., & Monteggia, L. M. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-023-01629-w · Cited by 262
Ketamine: A tale of two enantiomers
Jelen, L. A., Young, A. H., & Stone, J. M. (2020) · Journal of Psychopharmacology · doi:10.1177/0269881120959644 · Cited by 266
“Finally, in patients with TRD, concurrent use of buprenorphine and methadone (high affinity mu opioid receptor agonists) was not associated with reductions in antidepressant efficacy of (R,S)-ketamine (Marton et al., 2019).”
BackgroundMethodInfluentialThe role of dissociation in ketamine’s antidepressant effects
Ballard, E. D., & Zarate, C. A. (2020) · Nature Communications · doi:10.1038/s41467-020-20190-4 · Cited by 231
Esketamine 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-citationMatveychuk, D., Thomas, R. K., Swainson, J., Khullar, A., MacKay, M.-A., Baker, G. B., & Dursun, S. M. (2020) · Therapeutic Advances in Psychopharmacology · doi:10.1177/2045125320916657 · Cited by 209
Pitsillou, E., Bresnehan, S. M., Kagarakis, E. A., Wijoyo, S. J., Liang, J., Hung, A., & Karagiannis, T. C. (2020) · Molecular Biology Reports · doi:10.1007/s11033-019-05129-3 · Cited by 206
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
Mechanisms of ketamine and its metabolites as antidepressants
Hess, E. M., Riggs, L. M., Michaelides, M., & Gould, T. D. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114892 · Cited by 175
Ketamine Treatment for Depression: A Review
Yavi, M., Lee, H., Henter, I. D., Park, L. T., & Zarate, C. A. (2022) · Discover Mental Health · doi:10.1007/s44192-022-00012-3 · Cited by 161
New and emerging approaches to treat psychiatric disorders
Scangos, K. W., State, M. W., Miller, A. H., Baker, J. T., & Williams, L. M. (2023) · Nature Medicine · doi:10.1038/s41591-022-02197-0 · Cited by 164
Kohtala, S. (2021) · Pharmacological Reports · doi:10.1007/s43440-021-00232-4 · Cited by 155
“In addition, one study addressed intranasal S-ketamine combined with an oral antidepressant for relapse prevention [107].”
BackgroundMartinotti, 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
Self-citationRhee, T. G., Shim, S. R., Forester, B. P., Nierenberg, A. A., McIntyre, R. S., Papakostas, G. I., Krystal, J. H., Sanacora, G., & Wilkinson, S. T. (2022) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2022.3352 · Cited by 141
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
Gastaldon, 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
Self-citationToll-Like Receptor Signaling in Depression
Figueroa‐Hall, L. K., Paulus, M. P., & Savitz, J. B. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2020.104843 · Cited by 122
“MDD can be difficult to treat (Berton and Nestler, 2006; Daly et al., 2019) and has major effects on emotional and physical health, negatively impacting daily activities and social interactions.”
BackgroundLong-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
The 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
Jha, M. K., & Mathew, S. J. (2023) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20230025 · Cited by 121
Ketamine Assisted Psychotherapy: A Systematic Narrative Review of the Literature
Drozdz, S. J., Goel, A., McGarr, M. W., Katz, J. D., Ritvo, P., Mattina, G. F., Bhat, V., Diep, C., & Ladha, K. S. (2022) · Journal of Pain Research · doi:10.2147/jpr.s360733 · Cited by 117
“This is compounded by the significant time and financial costs to patients involved in the uptake of KAP.(15,48,49) Future research should build on our current understandings of the benefits of treatment and aim to improve efficacy and the duration of effects using larger sample sizes.”
BackgroundInfluentialShiroma, P. R., THURAS, P. D., Wels, J., Albott, C. S., Erbes, C. R., Tye, S. J., & Lim, K. O. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-00897-0 · Cited by 124
McIntyre, R. S., Rodrigues, N. B., Lee, Y., Lipsitz, O., Subramaniapillai, M., Gill, H., Nasri, F., Majeed, A., Lui, L. M. W., Senyk, O., et al. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.05.088 · Cited by 110
Swainson, J., McGirr, A., Blier, P., Brietzke, E. M., Richard‐Devantoy, S., Ravindran, N., Blier, J., Beaulieu, S., Frey, B. N., Kennedy, S. H., et al. (2020) · The Canadian Journal of Psychiatry · doi:10.1177/0706743720970860 · Cited by 124
Self-citationThe antidepressant actions of ketamine and its enantiomers
Johnston, J. N., Henter, I. D., & Zarate, C. A. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108431 · Cited by 112
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
Ketamine in neuropsychiatric disorders: an update
Johnston, J. N., Kadriu, B., Kraus, C., Henter, I. D., & Zarate, C. A. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-023-01632-1 · Cited by 108
Zheng, W., Cai, D.-B., Xiang, Y.-Q., Zheng, W., Jiang, W., Sim, K., Ungvari, G. S., Huang, X., Huang, X.-X., Ning, Y., et al. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.01.002 · Cited by 101
Intranasal Polymeric and Lipid-Based Nanocarriers for CNS Drug Delivery
Maher, R., Moreno-Borrallo, A., Jindal, D., Mai, B. T., Ruiz‐Hernández, E., & Harkin, A. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15030746 · Cited by 104
Jelen, L. A., & Stone, J. M. (2021) · International Review of Psychiatry · doi:10.1080/09540261.2020.1854194 · Cited by 112
“…were randomized in the maintenance phase, those who continued treatment with intermittently administered (S)-ketamine nasal spray plus an oral antidepressant had a significantly delayed time to relapse compared to those treated with placebo nasal spray and oral antidepressant (Daly et al., 2019).”
MethodResultFunctional neuroimaging in psychiatry and the case for failing better
Nour, M. M., Liu, Y., & Dolan, R. J. (2022) · Neuron · doi:10.1016/j.neuron.2022.07.005 · Cited by 92
Mathai, D. S., Meyer, M. J., Storch, E. A., & Kosten, T. R. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.12.023 · Cited by 97
Gill, H., Gill, B., Rodrigues, N. B., Lipsitz, O., Rosenblat, J. D., El-Halabi, S., Nasri, F., Mansur, R. B., Lee, Y., & McIntyre, R. S. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.11.020 · Cited by 93
Perspectives for therapy of treatment‐resistant depression
Papp, M., Cubała, W. J., Święcicki, Ł., Newman‐Tancredi, A., & Willner, P. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15596 · Cited by 96
Self-citationCanuso, C. M., Ionescu, D. F., Li, X., Qiu, X., Lane, R., Turkoz, I., Nash, A. I., Lopena, T. J., & Fu, D. (2021) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000001465 · Cited by 89
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
“059) in the esketamine nasal spray arm compared with placebo Response and remission rates were higher in the esketamine nasal spray arm compared with the placebo arm ESKETINTRD3003 NCT02493868 (Daly et al. 2019) Randomised, double-blind, withdrawal study of adults (18–64 years) with TRD 619 145 Esketamine nasal spray…”
BackgroundMethodInfluentialSelf-citationEsketamine: A Novel Option for Treatment-Resistant Depression
Bozymski, K. M., Crouse, E. L. B., Titus-Lay, E. N., Ott, C. A., Nofziger, J. L., & Kirkwood, C. K. (2019) · Annals of Pharmacotherapy · doi:10.1177/1060028019892644 · Cited by 82
Esketamine 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
“These side effects were of moderate or mild intensity, being detected especially following administration of the medication and typi‑ cally remitted on the same day (40,41).”
InfluentialNovel 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
Ketamine: Neuroprotective or Neurotoxic?
Choudhury, D., Autry, A. E., Tolias, K. F., & Krishnan, V. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.672526 · Cited by 89
Psilocybin and MDMA for the treatment of trauma-related psychopathology
Bird, C., Modlin, N. L., & Rucker, J. (2021) · International Review of Psychiatry · doi:10.1080/09540261.2021.1919062 · Cited by 94
“…as a treatment for MDD given in combination with an SSRI, demonstrating rapid and sustained antidepressant effects within hours of intranasal administration (Daly et al., 2019; Fedgchin et al., 2019; Murrough et al., 2013; Ochs-Ross et al., 2018; Popova et al., 2019; Wilkinson et al., 2018).”
BackgroundEfficacy and safety of intranasal esketamine for the treatment of major depressive disorder
Kryst, J., Kawalec, P., & Pilc, A. (2019) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2019.1683161 · Cited by 78
“The most common adverse events (>10%) in the esketamine group during the maintenance phase were dysgeusia, vertigo, dissociation, drowsiness, dizziness, headache, nausea, blurred vision, and oral hypoesthesia [45].”
BackgroundLoo, 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
Ketamine and nitrous oxide: The evolution of NMDA receptor antagonists as antidepressant agents
Kalmoe, M. C., Janski, A. M., Zorumski, C. F., Nägele, P., Palanca, B. J. A., & Conway, C. R. (2020) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2020.116778 · Cited by 78
Gliwińska, A., Czubilińska-Łada, J., Więckiewicz, G., Świętochowska, E., Badeński, A., Dworak, M., & Szczepańska, M. (2023) · Brain Sciences · doi:10.3390/brainsci13020163 · Cited by 85
“showed in their randomized clinical trial that, when compared with treatment with antidepressants and placebo, (S)-ketamine nasal spray and antidepressant treatment reduced the risk of relapse by 51% in patients who achieved stable remission and by 70% in those who achieved stable response [59].”
BackgroundResultKrystal, J. H., Kaye, A. P., Jefferson, S., Girgenti, M. J., Wilkinson, S. T., Sanacora, G., & Esterlis, I. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2305772120 · Cited by 83
“Responders who stopped Esketamine but continued their antidepressant had a relapse rate of over 57% (55).”
BackgroundSignature-based approaches for informed drug repurposing: targeting CNS disorders
Shukla, R., Henkel, N., Alganem, K., Hamoud, A.-R. A., Reigle, J. K., Alnafisah, R. S., Eby, H., Imami, A. S., Creeden, J. F., Miruzzi, S. A., et al. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0752-6 · Cited by 66
Nikkheslat, N. (2021) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2021.100383 · Cited by 72
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
Esketamine: a glimmer of hope in treatment-resistant depression
Kaur, U., Pathak, B. K., Singh, A., & Chakrabarti, S. S. (2019) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-019-01084-z · Cited by 70
Shen, 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
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
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
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
Self-citationA New Rapid-Acting Antidepressant
Krystal, J. H., Charney, D. S., & Duman, R. S. (2020) · Cell · doi:10.1016/j.cell.2020.02.033 · Cited by 63
Page, C. E., Epperson, C. N., Novick, A. M., Duffy, K. A., & Thompson, S. M. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02625-2 · Cited by 80
Glue, P., Loo, C. K. A., Fam, J., Lane, H., Young, A. H., Surman, P., BEDROC study investigators, Glozier, N., Fitzgerald, P. B., Liu, D., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-03063-x · Cited by 72
A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings
McInnes, L. A., Qian, J. J., Gargeya, R. S., DeBattista, C., & Heifets, B. D. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.12.097 · Cited by 63
Chronic administration of ketamine induces cognitive deterioration by restraining synaptic signaling
Luo, Y., Yang, Y., Zhang, M., He, H., & Fan, N. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0793-6 · Cited by 62
“antidepressant than when used for other purposes [8, 9]; thus,”
BackgroundSeo, M. K., Jeong, S., Seog, D., Lee, J. A., Lee, J.-H., Lee, Y. L., McIntyre, R. S., Park, S. W., & Lee, J. G. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.12.089 · Cited by 65
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-citationYang, S. Q., Zhou, Y., Yang, S. T., Mao, X., Chen, L., Bai, Z.-H., Ping, A. Q., Xu, S. Y., Li, Q. W., Gao, K., et al. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.07.007 · Cited by 58
Takahashi, N., Yamada, A., Shiraishi, A., Shimizu, H., Goto, R., & Tominaga, Y. (2021) · BMC Psychiatry · doi:10.1186/s12888-021-03538-y · Cited by 57
Kawczak, P., Feszak, I. J., & Bączek, T. (2024) · Biomedicines · doi:10.3390/biomedicines12102283 · Cited by 66
The economics of psychedelic-assisted therapies: A research agenda
Marseille, E. A., Bertozzi, S., & Kahn, J. G. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.1025726 · Cited by 62
McQuaid, 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
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
“There were no new safety signals during the ATUc period compared with the Phase 3 clinical trial data for esketamine (Daly et al. 2019; Fedgchin et al. 2019; Popova et al. 2019; Ochs-Ross et al. 2020; Wajs et al. 2020).”
ResultAre we repeating mistakes of the past? A review of the evidence for esketamine
Horowitz, M. A., & Moncrieff, J. (2021) · The British Journal of Psychiatry · doi:10.1192/bjp.2020.89 · Cited by 53
Opioid use disorder: current trends and potential treatments
Lee, Y. K., Gold, M. S., Blum, K., Thanos, P. K., Hanna, C., & Fuehrlein, B. (2024) · Frontiers in Public Health · doi:10.3389/fpubh.2023.1274719 · Cited by 59
Esketamine 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-citationStahl, S. M. (2020) · Cambridge University Press eBooks · doi:10.1017/9781108921275 · Cited by 52
Vekhova, K. A., Namiot, E. D., Jonsson, J., & Schiöth, H. B. (2024) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3478 · Cited by 61
Esketamine for treatment resistant depression: a trick of smoke and mirrors?
Gastaldon, C., Papola, D., Ostuzzi, G., & Barbui, C. (2020) · Epidemiology and Psychiatric Sciences · doi:10.1017/s2045796019000751 · Cited by 54
“5 points at MADRS between esketamine and placebo should be observed to make a claim of clinical significance (Daly et al., 2019), based on the results of phase II studies (Daly et al.”
BackgroundInfluentialReporting 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
“…AEs in the published articles were referring to only a single phase (most often induction) and did not provide any further information on AEs found in the other phases of the trial (Daly et al., 2018, 2019; Fedgchin et al., 2019; Ochs-Ross et al., 2020; Popova et al., 2019; Takahashi et al., 2021).”
BackgroundKetogenic diet for depression: A potential dietary regimen to maintain euthymia?
Włodarczyk, A., Cubała, W. J., & Stawicki, M. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110257 · Cited by 54
Self-citationNew and emerging treatments for major depressive disorder
Njenga, C., Ramanuj, P., de Magalhães, F. J. C., & Pincus, H. A. (2024) · BMJ · doi:10.1136/bmj-2022-073823 · Cited by 51
Feeney, A., & Papakostas, G. I. (2023) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2023.02.003 · Cited by 57
Enhanced ERK activity extends ketamine’s antidepressant effects by augmenting synaptic plasticity
Ma, Z., Guzikowski, N. J., Kim, J., Kavalali, E. T., & Monteggia, L. M. (2025) · Science · doi:10.1126/science.abb6748 · Cited by 54
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-citationPharmacotherapies 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
Approval of esketamine for treatment-resistant depression
Singh, J. B., Daly, E. J., Mathews, M., Fedgchin, M., Popova, V., Hough, D., & Drevets, W. C. (2020) · The Lancet Psychiatry · doi:10.1016/s2215-0366(19)30533-4 · Cited by 46
Self-citationSapkota, 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
“[22] using data from four randomized clinical trials [17-20] showed that Number Needed to Treat ( NNT) for efficacy outcome for esketamine vs placebo was less than 10, which indicates esketamine to be a potentially effective treatment for TRD.”
BackgroundMethodInfluentialKetamine in Major Depressive Disorder: Mechanisms and Future Perspectives
Shin, C., & Kim, Y. (2020) · Psychiatry Investigation · doi:10.30773/pi.2019.0236 · Cited by 47
Darcy, A., Beaudette, A., Chiauzzi, E., Daniels, J., Goodwin, K., Mariano, T. Y., Wicks, P., & Robinson, A. (2022) · Expert Review of Medical Devices · doi:10.1080/17434440.2022.2075726 · Cited by 40
“Pharmacological treatment Oral antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs); intravenous brexanolone for postpartum depression (PPD) [25]; intravenous ketamine for treatmentresistant depression (TRD); intranasal esketamine for TRD…”
BackgroundRetractedJohnson, C. R., Kangas, B. D., Jutkiewicz, E. M., Bergman, J., & Coop, A. (2022) · Biomedicines · doi:10.3390/biomedicines10020398 · Cited by 47
Sakurai, H., Jain, F. A., Foster, S. L., Pedrelli, P., Mischoulon, D., D, M. F. M., & Cusin, C. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.07.089 · Cited by 46
“In 2019, Janssen published controlled data regarding long-term efficacy and safety of administration of intranasal esketamine in 297 patients with TRD, followed for up to 92 weeks (Daly et al., 2019).”
BackgroundMethodAn Update on Glutamatergic System in Suicidal Depression and on the Role of Esketamine
Berardis, D. D., Tomasetti, C., Pompili, M., Serafini, G., Vellante, F., Fornaro, M., Valchera, A., Perna, G., Volpe, U., Martinotti, G., et al. (2020) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026620666200131100316 · Cited by 46
Ochs-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-citationSubcutaneous Ketamine in Depression: A Systematic Review
Cavenaghi, V. B., da Costa, L. P., Lacerda, A. L. T., Hirata, E. S., Miguel, E. C., & Fráguas, R. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.513068 · Cited by 44
“This led to FDA approval of intranasal (IN) esketamine for treating depression in 2019 (8, 9).”
BackgroundStrategies to Prolong Ketamine’s Efficacy in Adults with Treatment-Resistant Depression
McMullen, E. P., Lee, Y. L., Lipsitz, O., Lui, L. M. W., Vinberg, M., Ho, R., Rodrigues, N. B., Rosenblat, J. D., Cao, B., Gill, H., et al. (2021) · Advances in Therapy · doi:10.1007/s12325-021-01732-8 · Cited by 44
Ketamine for Treatment of Mood Disorders and Suicidality: A Narrative Review of Recent Progress
Kritzer, M. D., Mischel, N., Young, J. R., Lai, C. S., Masand, P. S., Szabo, S. T., & Mathew, S. J. (2021) · Annals of Clinical Psychiatry · doi:10.12788/acp.0048 · Cited by 43
Lenze, E. J., Nicol, G. E., Barbour, D. L., Kannampallil, T., Wong, A. W. K., Piccirillo, J., Drysdale, A. T., Sylvester, C. M., Haddad, R., Miller, J. P., et al. (2021) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.200042 · Cited by 43
Metadata
- Authors
- Daly, E. J., Trivedi, M. H., Janik, A., Li, H., Zhang, Y., Li, X., Lane, R., Lim, P., Duca, A. R., Hough, D., Thase, M. E., Zajecka, J., Winokur, A., Divacka, I., Fagiolini, A., Cubala, W. J., Bitter, I., Blier, P., Shelton, R. C., Molero, P., Manji, H., Drevets, W. C., & Singh, J. B.
- Affiliations
- Department of Neuroscience, Janssen Research and Development LLC, Titusville, New Jersey
- The University of Texas Southwestern Medical Center (US)
- Department of Neuroscience, Janssen Research and Development LLC, San Diego, California
- Department of Clinical Biostatistics, Janssen Research and Development LLC, Fremont, California
- Janssen Research & Development (United States) (US)
- Department of Clinical Biostatistics, Janssen Research and Development LLC, Titusville, New Jersey
- University of Pennsylvania (US)
- Rush University Medical Center (US)
- UConn Health (US)
- Private practice, Prague, Czech Republic
- University of Siena (IT)
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
- Semmelweis University (HU)
- University of Ottawa (CA)
- University of Alabama (US)
- Clinica Universidad de Navarra (ES)
- Corresponding author
- Daly, Ella J.
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2019-09-01
- Volume
- 76
- Issue
- 9
- Pages
- 893
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC6551577
- OpenAlex
- W2948816951
- Semantic Scholar
- a466e4d3128df9d49edb7484ee67fd7b3ab3d49c
- Cited by
- 795
- References
- 27
- Citations by year
- 2026: 98 · 2025: 110 · 2024: 104 · 2023: 81 · 2022: 69 · 2021: 79 · 2020: 236 · 2019: 16
- FWCI
- 61.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Funders
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Cancer Prevention and Research Institute of Texas
- Patient-Centered Outcomes Research Institute
- Sunovion
- Cerecor
- Otsuka America
- University of Oxford
- H. Lundbeck A/S
- Gobierno de Navarra
- Agency for Healthcare Research and Quality
- Allergan
- National Institute of Mental Health
- National Institute of Diabetes and Digestive and Kidney Diseases
- Janssen Research and Development
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pharmacology (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, treatment-resistant depression, relapse prevention, maintenance therapy, nasal spray, oral antidepressant, sustained remission, long-term efficacy, depression recurrence, ketamine
- MeSH terms
- Administration, Intranasal, Administration, Oral, Adult, Antidepressive Agents, Major Depressive Disorder, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Ketamine, Male, Middle Aged, Remission Induction, Outcome Assessment, Health Care, Secondary Prevention, Nasal Sprays, Depressive Disorder, Treatment-Resistant
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.
A language model drew the claims from the paper on 2026-10-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
