The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index; 8 of the 23 sources its claims cite were checked for support.
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study
Open accessAbstract
OBJECTIVE About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray. METHODS This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures. RESULTS Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was ob…
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Claims the paper makes
41 Own result · 13 Own method · 9 No full text of the sources · 6 Own interpretation · 5 Supported · 4 No basis given · 2 Sources not found · 1 Partly supported · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“Intravenous ketamine administered at subanesthetic doses was found to exhibit robust and rapid onset of efficacy in patients with treatment-resistant depression (9).”
What the sources say
- Supportedcites [9] source
The Study Design describes an intravenous infusion of 0.5 mg/kg ketamine in patients with major depressive disorder. The Comment reports a robust response within hours, and the Efficacy section reports a 71% response rate the day after infusion in the treatment-resistant sample. The supplied passages do not give page numbers. (LLM, conf=0.92)
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
Every source the paper cites for this claim was checked and supports it.
In the paper
“The odds ratio of 2.4 for response at day 28 in the esketamine plus oral antidepressant group was higher compared with odds ratios reported in a recent systematic review of antidepressant efficacy (34).”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
What the sources say
- Supportedcites [34] source
The Results report response-efficacy odds ratios of 1.37–2.13 for antidepressants versus placebo, all below the citing paper’s 2.4. The source does not report the esketamine result; the citation supports the comparison with its review findings. (LLM, conf=0.92)
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.
- 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
“likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points.”
plain- Asserted: passes — The authors put it forward as true.
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- 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
“Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=24.0,SE=1.69, 95% CI=27.31,20.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points.”
- Also stated in: § RESULTS · plain
“The mean MADRS score decreased from baseline to day 28, with greater improvement observed among those in the esketamine plus antidepressant arm as compared with the antidepressant plus placebo arm (difference of least square means=24.0,SE=1.69, 95% CI=27.31,20.64; p=0.020) (Table 2).”
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.
- Also stated in: § 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
“attenuated with repeated dosing (the mean change in CADSS score from before dosing to 40 minutes after dosing decreased from 7.8 [SE=0.84] on day 1 to 3.5 [SE=0.55] on day 25)”
- Also stated in: § DISCUSSION · plain
“evidence of attenuation of dissociation after repeated administrations, unlike esketamine's antidepressant efficacy, which was sustained”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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.
- Also stated in: § DISCUSSION · 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
“A total of 57.4% [66/115] and 10.1% [11/109] of patients in the esketamine and comparator arms, respectively, had a score #4 (moderate or greater sedation) on the Modified Observer's Assessment of Alertness/ Sedation at any postdose time during the double-blind treatment phase.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > RESULTS
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
“The number needed to harm for dissociation was 5 for the esketamine plus antidepressant arm compared with the antidepressant plus placebo arm.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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
“Six of 112 (5.4%) patients in the esketamine plus antidepressant arm and seven of 109 (6.4%) patients in antidepressant plus placebo arm had treatmentemergent postbaseline suicidal ideation.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > RESULTS
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
“and for patients in the antidepressant plus placebo arm, insomnia, irritability, and dysphoric mood/depression.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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.
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 number of patients meeting the full criterion for onset of clinical response by day 2 with persistence to day 28, a metric not evaluated in previous antidepressant drug or ketamine trials, was lower than anticipated.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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.
- Probably not a substantial claim. 14
- It may state two separate claims as one. 28
- The quote only partly states this claim. 5
Every source the paper cites for this claim was checked and supports it.
In the paper
“Research on mood disorder pathophysiology has implicated abnormalities in glutamatergic transmission, along with disrupted function and structure in neural circuits involved in mood regulation (4), findings that led to further investigation of glutamatergic N-methyl-D-aspartate (NMDA) receptor modulators in treating depression (5,6).”
What the sources say
- Supportedcites [4] source
The “Implications for Neurocircuitry-Based Models of Depression” section describes structural and functional abnormalities in a mood-related network and reports evidence of increased glutamatergic transmission in depression. “Recent Observations in Humans with Mood Disorders” likewise describes structural and functional alterations in implicated circuits. The later claim about investigating NMDA receptor modulators is attached to other citations, not this one. (LLM, conf=0.93)
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.
Probably not a substantial claim. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The sample size planned for this study was calculated assuming a treatment difference for the double-blind treatment phase of 6.5 points in MADRS score between the esketamine plus antidepressant group and the antidepressant plus placebo group and a standard deviation of 12, based on the results of a phase 2 study of esketamine nasal spray for treatment-resistant depression (11) and clinical”
- Also stated in: § Sample size determination. · plain
“Randomization of 98 individuals to each treatment group was required to achieve 90% power.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > Sample size determination.
What the sources say
- Supportedcites [11] source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plainn = 98- 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.
- Also stated in: § Sample size determination. · plain
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Earlier studies of esketamine in patients with treatmentresistant depression (10,11) and major depression at imminent risk for suicide (12), which demonstrated greater magnitude of early response, applied a less stringent definition for response onset and employed site-based raters for efficacy evaluation.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
What the sources say
- Supportedcites [10] source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [11] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [12] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
boostedcorrelational- 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.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The magnitude of postdose blood pressure increases was lower compared with the previous phase 2 study of esketamine nasal spray (11), possibly because of the riskmitigation blood pressure guidelines initiated in phase 3 studies (see the online supplement).”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
What the sources say
- Supportedcites [11] source
The cited paper is the earlier intranasal esketamine study, and its Safety section reports transient postdose blood-pressure increases, with maximum mean changes of 19.0 mm Hg systolic and 10.3 mm Hg diastolic. The citation is attached to that earlier study; the proposed explanation involving phase 3 risk-mitigation guidelines is attributed to the citing paper’s online supplement, not to this source. No page number is available in our copy. (LLM, conf=0.90)
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.
- 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
“Response was rapid in onset and increased over time during repeated dosing, with least square mean between-group differences, favoring esketamine, of 23.3 (95% CI=25.75, 20.85) 24 hours after dosing (i.e., at the day 2 visit), 22.9 (95% CI=25.17,20.59) at day 8, 22.0 (95% CI=24.78,0.82) at day 15, 23.8 (95% CI=26.87,20.65) at day 22, and, as noted above, 24.0 (95% CI=27.31,20.64) at day 28 (p=0.02”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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.
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
“Difference of LS | -4.0 | 1.69 | | |”
- Also stated in: § DISCUSSION · plain
“95% CI on difference -7.31, -0.64”
- Also stated in: § DISCUSSION · plain
“2-sided p value | 0.020”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
plainn = 201 ·- 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.
The quote only partly states this claim.
- Also stated in: § DISCUSSION · 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
“Nine patients experienced one or more adverse events leading to discontinuation of intranasal study drug during the double-blind treatment phase, eight (of 115, 7.0%) in the esketamine plus antidepressant arm (single events of anxiety, depression, depressive symptoms, panic attack, drug intolerance, feeling drunk, dizziness, headache, vertigo, nausea, road traffic accident, and multiple injuries)”
- Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · plain
“7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > RESULTS
plainn = 9- 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.
The quote only partly states this claim.
- Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · plain
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
“Generally, for patients who experienced sedation, this symptom started around 15 minutes into dosing and peaked at 30 to 45 minutes after dosing, and symptoms of sedation spontaneously resolved by 1 to 1.5 hours after dosing.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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 and transient perceptual effects measured by the CADSS (see Figure S5 in the online supplement) began shortly after the start of esketamine dosing, peaked at 40 minutes, generally resolved by 1.5 hours, and attenuated with repeated dosing”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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 adverse events were of mild or moderate severity and were transient, with onset shortly after dosing and resolution by 1.5 hours after dosing, while patients were in the clinic.”
- Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · hedged
“Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > RESULTS
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.
- Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · hedged
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
“At day 28, 53 of 101 (52.5%) and 31 of 100 (31.0%) patients in the respective treatment groups were in remission, with an NNT of 5 for remission.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > RESULTS
plaindirectn = 101- 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 post hoc analyses, the proportion of patients who at a given time point were responders and in remission in both treatment groups generally increased over time during the double-blind treatment phase, with 70 of 101 patients (69.3%) in the esketamine plus antidepressant arm and 52 of 100 patients (52.0%) in the antidepressant plus placebo arm being responders at day 28 (odds ratio=2.4,95% cred”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > RESULTS
plaincorrelationaln = 101- Asserted: passes — The authors put it forward as true.
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- 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
“One patient in the esketamine plus antidepressant arm experienced multiple injuries in a road traffic (motorbike) accident (reported as serious adverse events) on day 16 of the double-blind treatment phase (approximately 28 hours after an esketamine dose) and subsequently died on day 55, 40 days after the last dose of esketamine (additional information is provided in the online supplement).The”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > RESULTS
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
“Transient blood pressure increases occurred after each dose of esketamine; the maximum value was reached at 40 minutes after dosing in most cases and typically returned to or near the predose range by 1.5-2 hours after dosing (see Figure S3 in the online supplement).”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > RESULTS
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.
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
“During the double-blind treatment phase, the five most common treatment-emergent adverse events observed among patients in the esketamine plus antidepressant arm were dizziness, dissociation, dysgeusia, vertigo, and nausea (incidences ranging from 20.9% to 26.1%); the incidence of each was two to 10 times lower in the antidepressant plus placebo arm (Table 3).”
- Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · plain
“The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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.
- Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · plain
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 proportion of responders at day 28 was comparable for patients who experienced dissociation (maximum CADSS score .4 on day 1) and those who did not (maximum CADSS score #4 on day 1), with response rates of 68.5% and 70.2%, respectively.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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
“No notable differences were observed between patients using concomitant benzodiazepines compared with those not using benzodiazepines.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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
“Median CGI-S scores improved from baseline to endpoint of the double-blind treatment phase in both groups, with a median change from baseline of 22.0 (range=25 to 1; interquartile range=2) in the esketamine plus antidepressant arm and 22.0 (range=25 to 1; interquartile range=3) in the antidepressant plus placebo arm (see Table S6 in the online supplement).”
- Also stated in: § RESULTS · hedged
“The ANCOVA analysis based on the ranks of change showed a numerical difference favoring the esketamine arm over the comparator arm, with an odds ratio of 2.8 (95% credible interval=1.14, 7.68), suggesting that the odds of an improved CGI-S score at endpoint for patients in the esketamine arm were 2.8 times the odds for patients in the comparator arm.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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. The quote only partly states this claim.
- Also stated in: § RESULTS · hedged
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
“nocebo response (i.e., adverse effect following an”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
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.
The quote only partly states this claim.
In the paper
“The response and remission rates seen in the antidepressant plus placebo arm were higher than those reported in the Sequenced Treatment Alternatives to Relieve Depression trial for step 3 (response rate, 16.8%; remission rate, 13.7%) and in the olanzapine-fluoxetine study (33)”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [33] 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.
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
“However, in post hoc analyses, the results from both patient-reported outcomes showed consistency with the primary clinicianbased outcome result (see Figure S6 in the online supplement), providing supportive evidence from patients' perspective of improvement in mood and function after 4 weeks of treatment.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
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.
In the paper
“About 30% of patients with major depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression (2).”
- Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · plain
“About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants.”
What the sources say
- Not checked — no full text of the sourcecites [2] source
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.
- Also stated in: § Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study · plain
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
“To maintain blinding, a bittering agent was added to the intranasal placebo to simulate the taste of the esketamine solution, and three devices were administered to all patients at all sessions”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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. 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
“A delta adjustment tipping point sensitivity analysis was performed to evaluate the robustness of the MMRM analysis to increasing deviations from the missing-at-random assumption (results are presented in the online supplement).”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > Statistical Analysis
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
“Of 435 patients screened, nine (randomized at one site in Poland) were excluded from all analyses because of Good Clinical Practices violations (sensitivity analyses including this site confirmed no impact on the overall conclusions of the study), 227 underwent randomization to treatment; of these, three did not receive any study drug and one did not receive a dose of oral study antidepressant.”
- Also stated in: § RESULTS · plain
“Most randomized patients (197/227, 86.8%) completed the 28-day double-blind treatment phase (see Figure S1 in the online supplement).”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > RESULTS
plainn = 435- 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. The quote only partly states this claim.
- Also stated in: § RESULTS · plain
In the paper
“Ketamine (an NMDA receptor antagonist) affects fast excitatory glutamate transmission, increases release of brain-derived neurotrophic factor, and stimulates synaptogenesis (7).”
What the sources say
- Not checked — no full text of the sourcecites [7] 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. 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
“A serial gatekeeping (fixed sequence) approach was applied to adjust for multiplicity and to strongly control type I error across the primary and the three key secondary efficacy endpoints-namely, onset of clinical response by day 2, change in Sheehan Disability Scale score, and change in PHQ-9 score.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > Statistical Analysis
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
“Early clinical evidence suggested a potential role of ketamine in the treatment of depression, with mood-elevating effects observed in challenge studies (8).”
What the sources say
- Not checked — no full text of the sourcecites [8] source
hedgedconditional- 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.
In the paper
“In patients who respond to antidepressants, the time to onset of effect is typically several weeks, during which time patients remain symptomatic and at risk of suicidal behavior and self-harm (3).”
What the sources say
- Not checked — no full text of the sourcecites [3] 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
“In phase 2 studies, esketamine nasal spray demonstrated rapid onset and persistent efficacy in patients with treatment-resistant depression as well as in depressed patients at imminent risk for suicide (10)(11)(12).”
What the sources say
- Not matchedcites (10)(11)(12)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosteddirect- 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 only medication approved for the treatment of treatment-resistant depression is olanzapine plus fluoxetine, which has an NNT of 8 for response and 13 for remission (35).”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [35] source
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 claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“which is considered a clinically meaningful treatment difference (26,27) suggesting rapid onset of antidepressant efficacy.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
What the sources say
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.
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
“it is noteworthy that the dissociation ratings (CADSS scores) increased in the control group who received placebo nasal spray, providing evidence of adequate blinding and supporting expectation of benefit as one of the contributing factors of the higher than anticipated placebo response observed in the control group.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
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.
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
“While eventual efficacy bias was mitigated by using independent remote MADRS raters, it is possible that the specific adverse event profile of esketamine affected the blind for the study patients.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
hedgedconditional- 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
“A number of factors may have contributed to the smaller than anticipated effect size finding, the lower treatment difference compared with our phase 2 work, and the higher response and remission rates observed for the oral antidepressant plus placebo group”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
hedgedconditional- 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
“Because this trial was a flexible-dose study, dose-response relationships were not evaluated.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
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.
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
“Based on the predefined testing sequence, the other two key secondary endpoints (change in Sheehan Disability Scale and PHQ-9 scores) could not be formally evaluated.”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > DISCUSSION
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
“use of a newly initiated antidepressant (to which the patients had not shown a previous nonresponse) in the comparator arm (i.e., not a true placebo control)”
§ Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study > 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.
The paper relies on this without support.
Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability.
“Current treatment options for treatmentresistant depression have considerable limitations in terms of efficacy and patient acceptability.”
The paper relies on this without support.
There is a need to develop novel treatments that provide rapid relief of depressive symptoms, especially in patients with treatment-resistant depression.
“There is a need to develop novel treatments that provide rapid relief of depressive symptoms, especially in patients with treatment-resistant depression.”
The paper relies on this without support.
Esketamine has a higher affinity for the NMDA receptor than the R-enantiomer.
“Esketamine, the S-enantiomer of ketamine racemate, with a higher affinity for the NMDA receptor than the R-enantiomer, was recently approved by the U.S. Food and Drug Administration for treatment-resistant depression in adults.”
The authors state this as an assumption.
The missing data are missing at random.
“A delta adjustment tipping point sensitivity analysis was performed to evaluate the robustness of the MMRM analysis to increasing deviations from the missing-at-random assumption (results are presented in the online supplement).”
The paper relies on this without support.
Esketamine exhibits transient dissociative effects that are difficult to blind.
“Because esketamine exhibits transient dissociative effects that are difficult to blind, possibly biasing the site staff supervising the dosing, all MADRS assessments (used for the primary endpoint, the first key secondary endpoint, and calculation of response and remission rates) were performed by independent, remote (by telephone) raters who were blind to the protocol details, including study vis”
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
“Clinical trials found that esketamine, in combination with an oral antidepressant, rapidly reduced suicidal thoughts compared to placebo in adults with TRD who were at imminent risk for suicide [65,88,89].”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [65]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“A phase III trial of over 200 patients using esketamine adjunctive to an antidepressant demonstrated significant improvement in depression at 4 weeks compared with those using a placebo nasal spray.70”
From Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers (2020) · cites this paper as [70]
The cited source says what the claim attributes to it.
In the citing paper
“Among the three pivotal trials, one (NCT02418585 [11]) demonstrated positive results on its primary endpoint, while two (NCT02417064 [9] and NCT02422186 [10]) did not meet their primary endpoints.”
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
“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 [110]
In the citing paper
“Results from two 28-day phase III RCTs support multi-dose, adjunctive esketamine’s tolerability and AD efficacy in adult and geriatric samples [109,110].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [110]
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].”
Citations
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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
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“Moreover, intranasal administration is a non-invasive and well-tolerated means of drug delivery which has recently gained increasing interest as an administration route for psychotropic agents, such as esketamine for treatment-resistant depression [65].”
BackgroundIntravenous arketamine for treatment-resistant depression: open-label pilot study
Leal, G. C., Bandeira, I. D., Correia-Melo, F. S., Telles, M., Mello, R. P., Vieira, F., Lima, C. S., Jesus-Nunes, A. P., Guerreiro-Costa, L. N. F., Marback, R. F., et al. (2021) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-020-01110-5 · Cited by 257
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“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).”
BackgroundInfluentialEsketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression
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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
“The TRANSFORM-2 study was a four-week, randomized, placebo-controlled, double-blind Phase 3 clinical trial (n = 223) that included an antidepressant medication taper and randomization to either twice-weekly intranasal esketamine, flexibly dosed at 56 or 84 mg, or a placebo nasal spray, both administered in conjunction…”
MethodKryst, J., Kawalec, P., Mitoraj, A. M., Pilc, A., Lasoń, W., & Brzostek, T. (2020) · Pharmacological Reports · doi:10.1007/s43440-020-00097-z · Cited by 159
Esketamine for treatment-resistant depression: seven concerns about efficacy and FDA approval
Turner, E. H. (2019) · The Lancet Psychiatry · doi:10.1016/s2215-0366(19)30394-3 · Cited by 156
Esketamine for treatment resistant depression
Swainson, J., Thomas, R. K., Archer, S., Chrenek, C., MacKay, M.-A., Baker, G., Dursun, S., Klassen, L. J., Chokka, P., & Demas, M. L. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1640604 · Cited by 151
“to a statistically significant positive trial [66,69].”
BackgroundNew 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
Pharmacological Treatments for Patients with Treatment-Resistant Depression
Ruberto, V. L., Jha, M. K., & Murrough, J. W. (2020) · Pharmaceuticals · doi:10.3390/ph13060116 · Cited by 160
“, 2019 [83] Esketamine; placebo Fedgchin et al.”
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
Kohtala, S. (2021) · Pharmacological Reports · doi:10.1007/s43440-021-00232-4 · Cited by 155
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-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
“4 mmHg, respectively, at 40 minutes after the treatment, generally resolving by 1–2 hours [13,14].”
BackgroundThe 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
Acevedo-Diaz, E. E., Cavanaugh, G. W., Greenstein, D., Kraus, C., Kadriu, B., Zarate, C. A., & Park, L. T. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.11.028 · Cited by 113
“These findings are consistent with previous reports of SEs associated with intravenous ketamine and with the SE profile of intranasal esketamine (Popova et al., 2019).”
ResultShiroma, 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
The 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
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
“With regard to esketamine in particular, clinical use was largely based on four positive Phase 3 ef fi cacy studies [62 – 65] that informed the subsequent FDA approval of intranasal esketamine for TRD and suicidal ideation with intent, as described above.”
MethodResultKantrowitz, J. T., Dong, Z., Milak, M. S., Rashid, R., Kegeles, L. S., Javitt, D. C., Lieberman, J. A., & John Mann, J. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01541-1 · Cited by 100
Turkoz, I., Alphs, L., Singh, J., Jamieson, C., Daly, E., Shawi, M., Sheehan, J. J., Trivedi, M. H., & Rush, A. J. (2021) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.13260 · Cited by 104
Self-citationA Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics
Savalia, N. K., Shao, L.-X., & Kwan, A. C. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2020.11.008 · Cited by 104
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
Jelen, L. A., & Stone, J. M. (2021) · International Review of Psychiatry · doi:10.1080/09540261.2020.1854194 · Cited by 112
“…dosing, significant reductions in depressive symptoms have been shown at 1week (Daly et al., 2018), day 11 (Canuso et al., 2018) and up to 4weeks (Popova et al., 2019), however other studies have failed to show significant differences at the 4week time point (Canuso et al., 2018; Fedgchin et…”
BackgroundResultCeban, F., Rosenblat, J. D., Kratiuk, K., Lee, Y. L., Rodrigues, N. B., Gill, H., Subramaniapillai, M., Nasri, F., Lui, L. M. W., Lipsitz, O., et al. (2021) · CNS Drugs · doi:10.1007/s40263-021-00846-5 · Cited by 98
Expectancy in placebo-controlled trials of psychedelics: if so, so what?
Butler, M., Jelen, L., & Rucker, J. (2022) · Psychopharmacology · doi:10.1007/s00213-022-06221-6 · Cited by 100
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
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
Dean, R. L., Hurducas, C., Hawton, K., Spyridi, S., Cowen, P. J., Hollingsworth, S., Marquardt, T., Barnes, A., Smith, R., McShane, R., et al. (2021) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd011612.pub3 · Cited by 95
A Word to the Wise About Intranasal Esketamine
Schatzberg, A. F. (2019) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19040423 · Cited by 96
Vázquez, G. H., Bahji, A., Undurraga, J., Tondo, L., & Baldessarini, R. J. (2021) · Journal of Psychopharmacology · doi:10.1177/02698811211013579 · Cited by 95
Scott, F., Hampsey, E., Gnanapragasam, S., Carter, B., Marwood, L., Taylor, R. W., Emre, C., Korotkova, L., Martín-Dombrowski, J., Cleare, A. J., et al. (2023) · Journal of Psychopharmacology · doi:10.1177/02698811221104058 · Cited by 87
“Although in our review we find that dissociation is reported with greater frequency in the (es)ketamine group in some studies (Fedgchin et al., 2019; Popova et al., 2019), generally, tolerability is poorly reported across investigations of (es)ketamine (Ionescu et al.”
ResultFunctional 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
Dodd, 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
Canuso, 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-citationKasper, 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
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
“Another phase III study, TRANSFORM‑2, had a double‑blind, randomized, multicenter, active comparator design, and 227 patients with moderate/severe MDD who did not respond to ≥2 antidepressants were enrolled (25,26).”
InfluentialEsketamine: 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
“Dissociation was transient and resolved with repeated dosing.12-14 Elevations in blood pressure occurred and attenuated with infusion discontinuation.13 Studies also suggest that off-label IV ketamine may be useful in treatment-resistant bipolar depression and acute suicidal ideation.10,15 Esketamine nasal spray (Spra…”
BackgroundMethodInfluentialPsilocybin 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).”
BackgroundHudgens, S. A., Floden, L. L., Blackowicz, M. J., Jamieson, C., Popova, V., Fedgchin, M. M., Drevets, W. C., Cooper, K., Lane, R., & Singh, J. B. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.11.066 · Cited by 80
Self-citationEfficacy 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 in the esketamine group (reported in >10% of patients) were dysgeusia, nausea, vertigo, dizziness, headache, drowsiness, short-lived perceptual changes, blurred vision, paresthesia, and anxiety, while in the placebo group, dysgeusia and headache [43].”
BackgroundMartinotti, 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
“32 Furthermore, we found a dramatic increase in ESK-NS effectiveness from T1 to T2 (responders increased in the B-TRD group from 25.7% to 68.57%, in the TRD group from 25.7% to 57.14%), suggesting the presence of later responders.”
InfluentialLoo, 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
“Further, significant efficacy was demonstrated even with assessment of the primary outcome 3 days after the last treatment, rather than the next day as in other key studies 5 .”
BackgroundInfluentialKetamine 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
Bahji, A., Zarate, C. A., & Vázquez, G. H. (2022) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2022.2047928 · Cited by 78
“Across trials, six involved ketamine dose titration [94,95,99,100,115,119], while the rest had fixeddosing regimens.”
Emerging concepts on the use of ketamine for chronic pain
Yang, Y., Maher, D. P., & Cohen, S. P. (2020) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2020.1717947 · Cited by 73
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
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
“…esketamine versus placebo to treat TRD (Table 2), both adjunctive to a newly initiated oral SNRI or SSRI antidepressant, there was significantly greater improvement in the esketamine group at day 28 [ P 0.05 for adjunctive esketamine ( n = 114) versus adjunctive placebo ( n = 109)] [127].”
BackgroundInfluentialCaldiroli, 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
The role and mechanism of tryptophan – kynurenine metabolic pathway in depression
Gong, X., Chang, R., Zou, J., Tan, S., & Huang, Z. (2022) · Reviews in the Neurosciences · doi:10.1515/revneuro-2022-0047 · Cited by 72
Structural neural plasticity evoked by rapid-acting antidepressant interventions
Liao, C., Dua, A. N., Wojtasiewicz, C., Liston, C. M., & Kwan, A. C. (2024) · Nature reviews. Neuroscience · doi:10.1038/s41583-024-00876-0 · Cited by 81
“Ketamine, primarily an NMDAR antagonist 81 , has been studied at subanaesthetic doses and is an FDA-approved medication for treatment-resistant depression 20,82 .”
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-citationHiggins, G. A., Carroll, N. K., Brown, M., MacMillan, C., Silenieks, L. B., Thevarkunnel, S., Izhakova, J., Magomedova, L., DeLannoy, I., & Sellers, E. M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.640241 · Cited by 72
“A modest incidence of side effects including dizziness, sedation, nausea, attentional disturbance, hypertension is reported at the approved doses (Morrison et al., 2018; Popova et al., 2019; Salahudeen et al., 2020).”
BackgroundShen, 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
A 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
The emergence of ketamine as a novel treatment for posttraumatic stress disorder
Feder, A., Rutter, S., Schiller, D., & Charney, D. S. (2020) · Advances in pharmacology · doi:10.1016/bs.apha.2020.05.004 · Cited by 65
Chen, Y., Guo, Y., Wu, H., Tang, Y.-J., Sooranna, S. R., Zhang, L., Chen, T., Xie, X., Qiu, L., & Wu, X. (2024) · JAMA Network Open · doi:10.1001/jamanetworkopen.2024.0953 · Cited by 66
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
Vincenzo, J. D. D., Siegel, A. N., Lipsitz, O., Ho, R., Teopiz, K. M., Ng, J., Lui, L. M. W., Lin, K., Cao, B., Rodrigues, N. B., et al. (2021) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2021.02.058 · Cited by 64
Ketamine as a therapeutic agent for depression and pain: mechanisms and evidence
Subramanian, S., Haroutounian, S., Palanca, B. J. A., & Lenze, E. J. (2022) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2022.120152 · Cited by 73
An update on NMDA antagonists in depression
Pochwat, B., Nowak, G., & Szewczyk, B. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1643237 · Cited by 67
“However, clinically significant effects of the treatment were observed 24 hr after the first dose [107].”
BackgroundA 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
Leal, G. C., Souza-Marques, B., Mello, R. P., Bandeira, I. D., Caliman-Fontes, A. T., Carneiro, B. A., Faria-Guimarães, D., Guerreiro-Costa, L. N. F., Jesus-Nunes, A. P., Silva, S. S., et al. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.02.151 · Cited by 62
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-citationPettorruso, M., Guidotti, R., d’Andrea, G., Risio, L. D., D’Andrea, A., Chiappini, S., Carullo, R., Barlati, S., Zanardi, R., Rosso, G., et al. (2023) · Psychiatry Research · doi:10.1016/j.psychres.2023.115378 · Cited by 60
Maina, G., Adami, M., Ascione, G., Bondi, E., Berardis, D. D., Delmonte, D., Maffezzoli, S., Martinotti, G., Nivoli, A., Ottavianelli, E., et al. (2023) · Annals of General Psychiatry · doi:10.1186/s12991-023-00478-7 · Cited by 59
“I am satisfied with the efficacy of lithium and/or antipsychotics as augmentation therapies for patients with TRD 13.”
BackgroundKawczak, P., Feszak, I. J., & Bączek, T. (2024) · Biomedicines · doi:10.3390/biomedicines12102283 · Cited by 66
“Several Phase II and III trials showed that combining intranasal (S)-ketamine with an oral antidepressant was more effective than a placebo combined with oral antidepressants [58–61], though some studies did not show positive results [62,63].”
BackgroundTakahashi, N., Yamada, A., Shiraishi, A., Shimizu, H., Goto, R., & Tominaga, Y. (2021) · BMC Psychiatry · doi:10.1186/s12888-021-03538-y · Cited by 57
Heerlein, K., Young, A. H., Otte, C., Frodl, T., Degraeve, G., Hagedoorn, W., Oliveira-Maia, A. J., Pérez, V., Rathod, S., Rosso, G., et al. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.11.124 · Cited by 58
“While patients in TRANSFORM-2 reported, on average, a higher level of depression severity (as determined by total mean MADRS score), patient-reported outcomes, including HRQoL scores, were remarkably similar to those from the present observational study (Popova et al., 2019).”
ResultSamalin, 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).”
BackgroundResultInfluentialGrabski, M., Borissova, A., Marsh, B., Morgan, C. J. A., & Curran, H. V. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112629 · Cited by 55
Low dose oral ketamine treatment in chronic suicidality: An open-label pilot study
Can, A., Hermens, D. F., Dutton, M., Gallay, C. C., Jensen, E., Jones, M., Scherman, J. K., Beaudequin, D. A., Yang, C., Schwenn, P., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01230-z · Cited by 53
Are 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
“22 The MADRS scale goes from 0 to 60; average score for patients at baseline was 37.”
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
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
Immunotherapy for depression: Recent insights and future targets
Bai, Y., Cai, Y., Chang, D., Li, D., Huo, X., & Zhu, T. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108624 · Cited by 56
Stahl, S. M. (2020) · Cambridge University Press eBooks · doi:10.1017/9781108921275 · Cited by 52
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
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
“Four [15,16,20,21] studies used flexible doses while other four [17,19,29,30] used fixed doses of intranasal esketamine.”
BackgroundInfluentialChiappini, 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
Metadata
- Authors
- Popova, V., Daly, E. J., Trivedi, M., Cooper, K., Lane, R., Lim, P., Mazzucco, C., Hough, D., Thase, M. E., Shelton, R. C., Molero, P., Vieta, E., Bajbouj, M., Manji, H., Drevets, W. C., & Singh, J. B.
- Affiliations
- Janssen (Belgium) (BE)
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2019-06-01
- Volume
- 176
- Issue
- 6
- Pages
- 428-438
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- OpenAlex
- W2946661342
- Semantic Scholar
- 6b7c3525b179fffd83aabf69c45b1dca607faa4e
- Cited by
- 904
- References
- 32
- Citations by year
- 2026: 88 · 2025: 114 · 2024: 135 · 2023: 94 · 2022: 95 · 2021: 98 · 2020: 251 · 2019: 28
- FWCI
- 73.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Psychiatric Foundation
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Cancer Prevention and Research Institute of Texas
- AcademyHealth
- Yale University
- Patient-Centered Outcomes Research Institute
- Stanley Medical Research Institute
- Sunovion
- ACADIA Pharmaceuticals
- Sage Therapeutics
- Avanir Pharmaceuticals
- Cerecor
- Myriad Genetics
- Otsuka America
- University of Oxford
- Deutsche Forschungsgemeinschaft
- Generalitat de Catalunya (2014_ SGR_398)
- Gedeon Richter
- Universidad de Navarra
- Ministerio de Ciencia e Innovación
- Servier
- H. Lundbeck A/S
- Gobierno de Navarra
- National Institutes of Health
- Agency for Healthcare Research and Quality
- Allergan
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Institute of Diabetes and Digestive and Kidney Diseases
- Janssen Research and Development
- National Center for Advancing Translational Sciences
- Janssen Pharmaceuticals
- 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
- depression, esketamine, nasal spray, antidepressant switching, flexible dosing, rapid-acting antidepressants, antidepressant non-response, dissociation, adverse events, depression remission, treatment-resistant depression, antidepressant efficacy, nausea, vertigo, dysgeusia, dizziness, treatment discontinuation
- MeSH terms
- Duloxetine Hydrochloride, Venlafaxine Hydrochloride, Administration, Intranasal, Administration, Oral, Adult, Antidepressive Agents, Major Depressive Disorder, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Ketamine, Male, Middle Aged, Citalopram, Treatment Outcome, Sertraline, 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 ›
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