This page shows what was measured, who it was measured in, and what that does not settle.
What Esketamine does in the body
Depression that has not responded to at least two other antidepressants
Most antidepressants nudge serotonin and take weeks. Esketamine blocks a receptor for glutamate, the brain's main "go" signal, and does something different: within hours it appears to trigger a burst of new connections between nerve cells. The nasal spray is given in a clinic because the same receptor blockade also causes a temporary out-of-body feeling and a rise in blood pressure, and patients have to be watched for two hours afterwards.
What happened in people
A 4.0-point MADRS separation from placebo spray at day 28 in TRANSFORM-2
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The recorded finding that sits closest to something a person would notice. Written into the record, not signed off, and it carries no population or interval.
Administered only in REMS-certified settings with a two-hour observation period, which makes it a clinic service rather than a prescription
Where it acts
Cortical and hippocampal glutamatergic synapses; NMDA receptor channel pore
Kind of result
The kind of result is not recorded
Supervision
Professional supervision is normally required. A regulator classifies this substance in a way that restricts how it is supplied.
What the registries record it as
The substance registry classes this as chemical.
FDA substance registry · 50LFG02TXD · read 2026-08-29
Its recorded molecular formula is C13H16ClNO·HCl, weighing 274.2.
US prescribing information · d81a6a79-a74a-44b7-822c-0dfa3036eaed · read 2026-08-30
Where each sentence above came from
No recorded sentence describes the change this makes in a way that stands on its own. The page opens with what it is taken for instead, and the recorded explanation follows below.
Shown as the opening line on this page.
A limit recorded against this substance. Not signed off as a reviewed claim.
The four opening statements run to 97 words.
Words this page uses
Four words worth knowing first
Chosen from what this page shows, with each one explained before the word it depends on.
Comparator
A comparator is whatever the treatment was measured against.
A picture of it, and where the picture fails
It is like the other runner in a race.
Where that stops being true. A race has one winner. A study can show both arms improved.
What people get wrong. Results are read without asking what the other group got. Beating nothing is not beating a treatment.
The control condition against which the experimental intervention is assessed.
Randomisation
Randomisation means chance decides who gets which treatment.
A picture of it, and where the picture fails
It is like a coin toss deciding the groups.
Where that stops being true. A coin toss is fair once. Fairness here comes from doing it for everyone.
What people get wrong. It is thought to make groups identical. It makes them similar on average, including on things nobody measured.
Allocation of participants to arms by a chance process, so that unmeasured factors are balanced in expectation.
Absolute difference
An absolute difference is how many more people in a hundred were affected.
A picture of it, and where the picture fails
It is like counting heads in two rooms of a hundred.
Where that stops being true. Heads are easy to count. Study results carry a margin of error too.
What people get wrong. It is confused with a percentage change, which can look far larger.
The arithmetic difference in event rates between arms.
Confidence interval
A confidence interval is the range the true answer is likely to sit in.
A picture of it, and where the picture fails
It is like a weather forecast giving a range rather than one number.
Where that stops being true. A forecast range covers tomorrow. This one covers what the study could resolve.
What people get wrong. The middle number is read as the answer. A range crossing zero means no change is still possible.
An interval estimate that would contain the true parameter in a stated proportion of repeated studies.
What happened in people◇Read from sources, not yet reviewed
What happened in people
Each card is one study: the exact question it asked, who was in it, and whether it showed what it set out to show.
Change in MADRS total score from baseline to day 28
✓ The study showed what it set out to show
Who was studied
TRANSFORM-2 (NCT02418585)
How many people
227
Study design
Phase 3
Compared against
Not recorded for this study
Kind of result
A number that stands in for health
What was found
Difference of least-squares means -4.0 (SE 1.69, 95% CI -7.31 to -0.64)
Repeated elsewhere
Partially Replicated
What this does not prove. Meeting one endpoint in one population does not carry to other goals or other people.
The limits of this study, and where it came from
Main limit. Discontinuation for adverse events 7% versus 0.9%; dissociation, nausea, vertigo, dysgeusia and dizziness all more frequent on esketamine.
How far it carries. This study is recorded from the curated record, not from the registry match.
Form and route. Intranasal spray device, administered under supervision in a certified healthcare setting
Interval reported. 95% CI -7
Written into the record, not signed off as a reviewed claim.
RNAWiki holds 5 written-up human studies for this substance, each with the question it asked.
How we know it
Each card names the study, the number of people and what the study set out to measure.
What this does not prove
These summaries were written by a person and have not been signed off as reviewed claims.
Why it matters
A study that failed is as informative as one that worked, and both are here.
What we still do not know
No reviewed claim exists, so no exact population, effect size or interval is published yet.
What it changes in the body◇Read from sources, not yet reviewed
The path through the body
From what a person takes to what changes. A solid line is a step measured in people. A dashed line is a step nobody has measured that way.
Start
Esketamine
What a person takes: Intranasal spray device, administered under supervision in a certified healthcare setting.
The measurement behind this step
Single-use nasal spray devices delivering 28 mg each, used in combination to give 56 or 84 mg. Self-administered by the patient under direct observation, with blood pressure checked before and after and at least two hours of monitoring. It cannot be dispensed for home use.
Getting in
Sprayed into the nose, in a clinic
The dose is given as a nasal spray under supervision, and the patient stays for at least two hours.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
Intranasal administration bypasses first-pass metabolism, giving roughly 48% bioavailability and a peak plasma concentration within 20 to 40 minutes. Administration is restricted to REMS-certified healthcare settings with a minimum two-hour observation period after each dose.
It is small and greasy enough to cross into brain tissue almost immediately, which is why the effects start during the appointment.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
High lipophilicity and low protein binding give rapid central nervous system penetration. Metabolised principally by CYP2B6 and CYP3A4 to noresketamine, which retains some NMDA activity.
It slips into the open pore of a glutamate receptor and plugs it, preferentially on the receptors that are firing most.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Non-competitive open-channel block of the NMDA receptor, requiring the channel to be open to bind, which makes the block use-dependent. Esketamine has roughly three to four times the NMDA affinity of the R-enantiomer.
A glutamate burst, then new synapses — the part that is inferred
The leading explanation is that blocking these receptors on inhibitory cells releases a burst of glutamate that triggers the growth of new connections. Most of that evidence is from rodents.
──Measured in people. Written by a person from the study named beside the step. Not signed off as a reviewed claim.
The measurement behind this step
The prevailing model holds that preferential block of NMDA receptors on GABAergic interneurons disinhibits pyramidal cells, producing a glutamate surge that activates AMPA receptors, BDNF release, TrkB signalling and mTORC1-dependent synaptogenesis in prefrontal cortex. The rodent evidence for this cascade is substantial. Direct human evidence that it is the mechanism of the antidepressant effect is not.
Depression scores fall within hours, and dissociation does too
Improvement can appear within a day. So can the dissociation, nausea and blood pressure rise, and they usually pass within 90 minutes.
╌╌Described, with no measurement named. No measurement is named for this step, so it is drawn as an unconfirmed link.
The measurement behind this step
Measured endpoints are MADRS change at 24 hours and 28 days, and time to relapse. Dissociation, sedation, vertigo, dysgeusia, nausea and transient blood pressure elevation appear shortly after dosing and generally resolve by about 1.5 hours.
No suggested links are held for this record, so nothing is hidden from this path.
What we know
The record describes 5 steps from taking it to an effect in a person.
How we know it
Each step names the study behind it in the technical detail beside it.
What this does not prove
A change inside the body is a reason to look. It is not a result in a person.
Why it matters
A reader can see exactly where the chain stops being measured in people.
What we still do not know
No reviewed claim binds any of these steps to a named population.
What is missing or unclear◇Read from sources, not yet reviewed
Were people like you studied?
RNAWiki cannot tell whether a study fits you. It can show who was in it, and where the result stops carrying.
Who was studied
People similar to this profile were included.
Adults whose depression has not responded to at least two adequate trials of oral antidepressants. Administration is restricted to certified healthcare settings under a Risk Evaluation and Mitigation Strategy, with at least two hours of observation after each dose.
Who is missing from the studies
Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What the label states about particular groups
On pediatric, the label states: “The safety and effectiveness of SPRAVATO in pediatric patients have not been established.”
US prescribing information · d81a6a79-a74a-44b7-822c-0dfa3036eaed · read 2026-08-30
On older people, the label states: “The efficacy of SPRAVATO for the treatment of TRD in geriatric patients was evaluated in a 4-week, randomized, double-blind study comparing flexibly-dosed intranasal SPRAVATO plus a newly initiated oral antidepressant compared to intranasal placebo plus a newly initiated oral antidepressant in patients ≥ 65 years of age.”
US prescribing information · d81a6a79-a74a-44b7-822c-0dfa3036eaed · read 2026-08-30
On people who are pregnant, the label states: “Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including SPRAVATO, during pregnancy.”
US prescribing information · d81a6a79-a74a-44b7-822c-0dfa3036eaed · read 2026-08-30
On people who are breastfeeding, the label states: “Risk Summary Esketamine is present in human milk.”
US prescribing information · d81a6a79-a74a-44b7-822c-0dfa3036eaed · read 2026-08-30
On people with reduced liver function, the label states: “The mean esketamine AUC and t 1/2 values were higher in patients with moderate hepatic impairment compared to those with normal hepatic function [see Clinical Pharmacology (12.3) ] .”
US prescribing information · d81a6a79-a74a-44b7-822c-0dfa3036eaed · read 2026-08-30
Where the result stopped carrying
TRANSFORM-1: primary endpoint missed at 84 mg (P=0.088), with the 56 mg arm untestable under the fixed sequence
TRANSFORM-3: primary endpoint missed in patients aged 65 and older (P=0.059), with no signal at all above 75
ASPIRE: the suicidal ideation key secondary endpoint did not separate from placebo
This is a scope explorer, not a diagnosis engine.
It shows who was studied so you can see whether people similar to you were included.
RNAWiki cannot tell whether a study fits you. It can show who was in it.
What it would be like to take◇Read from sources, not yet reviewed
Why it might seem to do nothing
A real effect and a noticed effect are different things. These are the recorded reasons the two come apart.
It was studied in different people
The people in the studies were not much like the reader.
On this record: Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
The evidence may simply be wrong
Small early studies often do not hold up.
On this record: RNAWiki has not yet published a reviewed conclusion for this use.
Other reasons RNAWiki checked and found nothing for (11)
It was studied for a different goal
The studies measured something else entirely. Nothing in this record points to this reason.
A different form was studied
The studied form is not the form on the shelf. Nothing in this record points to this reason.
There was nothing to correct
Where a level is already normal, topping it up may change nothing. Nothing in this record points to this reason.
Something else had to happen too
In the studies it was paired with training, a diet or another treatment. Nothing in this record points to this reason.
The change is too small to feel
A real change can still sit below what a person notices. Nothing in this record points to this reason.
Day-to-day swing hides it
Sleep, food, stress and time of day move most numbers more than this would. Nothing in this record points to this reason.
Not enough time yet
The studies ran longer than the person has waited. Nothing in this record points to this reason.
It was not taken as studied
Missed days change the result, and studies count them. Nothing in this record points to this reason.
Something else changed at the same time
Two changes at once cannot be told apart afterwards. Nothing in this record points to this reason.
The product may not be what it says
Contents of a sold product are not always what the label states. Nothing in this record points to this reason.
No recorded reason
RNAWiki has nothing stored that would explain it. Nothing in this record points to this reason.
None of these is a reason to take more. Taking more is not a step this page ever suggests.
What it would be like to take◇Read from sources, not yet reviewed
What taking it involves
The recorded facts about getting hold of it and using it. Nothing here is a suggestion about what you should do.
How it is supplied
Prescription only
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Read from the recorded approval status.
No source is stored against this line.
Form and route
Intranasal spray device, administered under supervision in a certified healthcare setting
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form and route recorded on this substance.
No source is stored against this line.
Who oversees it
Professional supervision is normally required. A regulator classifies this substance in a way that restricts how it is supplied.
❝ Quoted from a source
Where this came from
Copied from a source RNAWiki stored, with the source named.
Suppression classes recorded: S1, S3, S5, S6.
No source is stored against this line.
What is in the pack
Single-use nasal spray devices delivering 28 mg each, used in combination to give 56 or 84 mg. Self-administered by the patient under direct observation, with blood pressure checked before and after and at least two hours of monitoring. It cannot be dispensed for home use.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on how this is sold and what that means for what is in the pack.
No source is stored against this line.
Where it is registered
Regulatory records are listed in the technical disclosure at the foot of this page.
# Counted from records
Where this came from
A count of rows RNAWiki holds. It describes our records, not your body.
Register entries are stored per jurisdiction and shown with their dates.
No source is stored against this line.
Why people stop
Not recorded.
∅ Nothing recorded
Where this came from
RNAWiki holds nothing here and says so rather than guessing.
No record of why people stopped taking it is stored for this substance.
No source is stored against this line.
What it would be like to take◇Read from sources, not yet reviewed
What can go wrong
Sorted by where each line came from. A regulator's label and a report somebody sent in are not the same kind of fact.
·Worth asking a clinician aboutWritten into the record from the studies named on this page
The US label carries a boxed warning covering sedation, dissociation, abuse and misuse, and increased risk of suicidal thoughts and behaviours; the product is available only through a restricted programme under a Risk Evaluation and Mitigation Strategy. Common adverse effects are dissociation, dizziness, nausea, sedation, vertigo, dysgeusia and transient blood pressure elevation. Esketamine is a Schedule III controlled substance in the United States.
Nobody counted how many people took this and were fine, so this cannot be turned into a rate.
Over a long time. No completed tested study window is recorded, so long-term effects are not established by the registry record.
Groups the studies covered thinly. Which groups were under-represented in the studies has not been recorded for this substance. Pregnancy, breastfeeding, children, older adults, and people with liver or kidney conditions are commonly excluded from trials; nothing here says whether they were.
What is missing or unclear◇Read from sources, not yet reviewed
Does the exact form matter?
Evidence belongs to the exact thing that was tested. A different salt, a different mixture or a different preparation is a different question.
The form that was studied
Intranasal spray device, administered under supervision in a certified healthcare setting
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
The form used in the studies cited on this page.
No source is stored against this line.
What is sold
Self-administered by the patient under direct observation, with blood pressure checked before and after and at least two hours of monitoring. It cannot be dispensed for home use.
✎ Source-linked record
Where this came from
A person wrote this into the record with the study named beside it. No reviewer has signed it off.
Recorded notes on which forms are sold and how they compare.
No source is stored against this line.
What is recorded as being sold
7 products list this as an active ingredient in the United States drug directory. 7 of them contain it and nothing else.
FDA National Drug Code directory · 54382-123 · read 2026-08-29
They are sold as powder and solution, taken nasal.
FDA National Drug Code directory · 54382-123 · read 2026-08-29
1 published label names it as an active ingredient. 1 of them describe this substance alone, which is where its own label text on this page comes from.
US prescribing information · d81a6a79-a74a-44b7-822c-0dfa3036eaed · read 2026-08-29
Those labels are classed as human prescription drug.
US prescribing information · d81a6a79-a74a-44b7-822c-0dfa3036eaed · read 2026-08-29
Spravato is nasal at 3 DOSAGE FORMS AND STRENGTHS Nasal Spray: 28 mg of esketamine per device., recorded as fda label in effect 2026-03-31 in the United States.
US prescribing information · d81a6a79-a74a-44b7-822c-0dfa3036eaed · read 2026-08-30
Evidence carries across two names for one substance. It does not carry across a salt, a mirror form or a mixture.
What it would be like to take◇Read from sources, not yet reviewed
What you could measure
This one is decided with a clinician, so this section holds questions to ask rather than a plan to run.
Self-experiment planning is not offered for a prescription or clinician-supervised medicine. The questions below are for a clinician or pharmacist.
Questions worth asking
Which of the trials of Esketamine studied people like me?
What was measured, and for how long?
Was the result a laboratory value or a health outcome?
What would we watch for, and when would we stop?
Tracking can show whether something changed for you. It cannot show what caused it.
RNAWiki records evidence. It does not say whether this substance is right for you.
What is missing or unclear◇Read from sources, not yet reviewed
Claims that go past the evidence
Things said about this substance that sound reasonable, and the exact step that is missing between the evidence and the claim.
✗Goes past the evidence
That the placebo-controlled effect sizes are uncontaminated by functional unblinding, when the drug produces unmistakable dissociation within minutes
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That esketamine reduces suicidal ideation — the ASPIRE key secondary endpoint on ideation did not reach significance, and the label claims depressive symptoms only
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
✗Goes past the evidence
That the rodent glutamate-burst and synaptogenesis cascade is the demonstrated human mechanism
Why it sounds right. It follows from something real on this page: a body step, an animal result or a related finding.
The missing step. Nobody measured this in people for this use, or the study that did measure it did not show it.
What would change this
A study in people, for this exact use, measuring this exact thing, that a reviewer signs off.
RNAWiki has not yet published a reviewed conclusion for this use.
What is missing or unclear◇Read from sources, not yet reviewed
What nobody knows yet
Open questions, each with why it is open and what would close it.
Missing populations
Which groups were under-represented in the studies has not been recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing long-term data
No completed tested study window is recorded.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
No reviewed conclusion
RNAWiki has not yet published a reviewed conclusion for this use.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Missing interaction studies
No interaction was found in the registers checked. Not finding one is not the same as showing there is none.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Formulation uncertainty
Several salts, forms or products of Esketamine are recorded. Results from one form may not transfer to another.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
Mechanism not reviewed
No reviewed mechanism story exists for this substance.
Why it matters. Recorded by the evidence model as a gap on this record.
What would answer it
A study that measures it, and a reviewer to sign it off.
Last checked 2026-09-04. Searched: The sources listed in the receipts at the foot of this page.
What happened in people◇Read from sources, not yet reviewed
Check any of this yourself
Every line above traced back to the study it came from. This is the technical layer, and the vocabulary changes here.
Every line above can be traced to the study named beside it. Follow the link and read it.
TRANSFORM-2: a 4.0-point MADRS separation at day 28
In plain words
The one short-term trial that succeeded showed depression scores four points lower on esketamine than on placebo spray at four weeks, on a 60-point scale.
What was measured
Change in MADRS total score from baseline to day 28
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Popova et al. (NCT02418585) randomised 227 of 435 screened patients with treatment-resistant depression to flexibly dosed esketamine nasal spray plus a newly initiated oral antidepressant, or to placebo spray plus a newly initiated antidepressant; 197 completed the 28-day double-blind phase. Difference of least-squares means on MADRS at day 28 was -4.0 (SE 1.69, 95% CI -7.31 to -0.64). The five most common adverse events were dissociation, nausea, vertigo, dysgeusia and dizziness, all more frequent on esketamine; 7% versus 0.9% discontinued for an adverse event. Events generally appeared shortly after dosing and resolved by 1.5 hours.
Written into the record, not signed off as a reviewed claim
Two of the three short-term trials missed their primary endpoint
In plain words
The fixed-dose trial and the trial in older adults both failed to reach statistical significance. Approval rested on the third.
What was measured
Change in MADRS total score at day 28, fixed-dose and elderly populations
Effect estimate
No reviewed effect estimate exists for this record.
Limits
This entry records a failure.
From the source
TRANSFORM-1 (Fedgchin et al., NCT02417064, 346 registered): esketamine 84 mg versus placebo gave an LS means difference of -3.2 (95% CI -6.88 to 0.45), two-sided P=0.088 — statistical significance not achieved, and because of the testing hierarchy the 56 mg arm could not be formally tested (nominal difference -4.1, P=0.027). TRANSFORM-3 (Ochs-Ross et al., NCT02422186, 139 elderly patients): median-unbiased treatment difference -3.6 (95% CI -7.20 to 0.07), z=1.89, two-sided P=0.059 — the authors state plainly that the primary endpoint was not achieved. Post-hoc, the effect was larger in patients aged 65 to 74 (-4.9, P=0.017 nominal) than in those 75 and older (-0.4, P=0.930).
Written into the record, not signed off as a reviewed claim
SUSTAIN-1: relapse risk cut by half to two thirds in patients who had already responded
In plain words
Among patients who got better on esketamine and then continued it, relapse over the following months was roughly half as likely as in those switched to placebo spray.
What was measured
Time to relapse after randomised withdrawal
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Daly et al. (NCT02493868) followed 297 adults into a randomised maintenance phase. Among 176 who achieved stable remission, relapse occurred in 24 of 90 (26.7%) on esketamine plus antidepressant versus 39 of 86 (45.3%) on antidepressant plus placebo (log-rank P=.003, NNT 6; HR 0.49, 95% CI 0.29 to 0.84). Among 121 with stable response, relapse occurred in 16 of 62 (25.8%) versus 34 of 59 (57.6%) (log-rank P<.001, NNT 4; HR 0.30, 95% CI 0.16 to 0.55). This is an enriched-withdrawal design: everybody randomised had already responded to esketamine, so the result describes maintenance, not initial efficacy.
Written into the record, not signed off as a reviewed claim
Functional unblinding: a dissociative drug cannot be reliably placebo-controlled
In plain words
Esketamine produces an unmistakable out-of-body sensation within minutes. Patients and raters can usually tell who got the real spray, which weakens every double-blind estimate in the programme.
What was measured
That the placebo-controlled MADRS differences in the esketamine programme measure a pharmacological effect uncontaminated by patients and raters knowing who received active drug
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Turner set out seven concerns about the approval: the reliance on a single positive short-term trial; the use of a two-of-three standard applied unevenly; the discontinuation-design maintenance trial being counted toward efficacy; the small absolute MADRS separations; deaths in the programme; the near-inevitable functional unblinding of a dissociative agent; and the choice of an active-comparator-free design. Horowitz and Moncrieff argued in the British Journal of Psychiatry that the field risks repeating past errors by treating a drug with obvious acute psychoactive effects as if it were blinded. Neither critique disputes that patients improved; both dispute how much of that improvement the placebo comparison can be trusted to isolate.
Written into the record, not signed off as a reviewed claim
ESCAPE-TRD: beat quetiapine head to head on remission at week 8
In plain words
Against the standard oral alternative, esketamine got more patients into remission at eight weeks — 27% against 18% — in a 676-patient randomised comparison.
What was measured
Remission (MADRS 10 or lower) at week 8
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Reif et al. (NCT04338321) randomised 336 patients to esketamine nasal spray plus an SSRI or SNRI and 340 to extended-release quetiapine plus an SSRI or SNRI. Remission at week 8 occurred in 91 of 336 (27.1%) versus 60 of 340 (17.6%), P=0.003. No relapse through week 32 after week-8 remission occurred in 73 of 336 (21.7%) versus 48 of 340 (14.1%). Over 32 weeks, remission, response and MADRS change all favoured esketamine. The trial was open-label by necessity — quetiapine and esketamine cannot be blinded against each other — which is a real limitation and also a reason it is not subject to the placebo-blinding objection.
Written into the record, not signed off as a reviewed claim
Suicidal ideation: rapid symptom reduction, no measured effect on the ideation itself
In plain words
In patients with active suicidal thoughts, esketamine reduced depression scores within a day. The suicidal ideation score itself did not separate from placebo.
What was measured
Change in MADRS total score at 24 hours; CGI-SS-r as key secondary
Effect estimate
No reviewed effect estimate exists for this record.
Limits
See the technical detail.
From the source
Fu et al. reported the ASPIRE I trial in patients with major depressive disorder and active suicidal ideation with intent. The primary endpoint, change in MADRS total score at 24 hours, favoured esketamine plus standard of care. The key secondary endpoint of change in the Clinical Global Impression of Severity of Suicidality did not reach statistical significance. The approved indication is therefore worded as depressive symptoms in patients with acute suicidal ideation or behaviour, and the label does not claim a reduction in suicidal ideation or in suicide.
This order is fixed in code and does not count clicks or time on the page.
What is not here
7 questions this page could not answer
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The older medicine-wide conclusion held in this record
Written for a clinical reader, and about the medicine as a whole rather than about one indication, population and set of trials. RNAWiki does not treat it as a programme conclusion and no reviewer has signed it off in that form. It is here word for word because it is what the record holds.
The first genuinely rapid-acting antidepressant to reach the market, approved on one positive short-term trial out of three, with a strong relapse-prevention result and a blinding problem that its critics argue makes the whole efficacy estimate uncertain.
Recorded evidence blocks (11)
Q2
On the Esketamine label: indicated for what?
"SPRAVATO is indicated for the treatment of: Treatment-resistant depression (TRD) in adults as monotherapy or in conjunction with an oral antidepressant Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior in conjunction with an oral antidepressant SPRAVATO is a…": indications and usage on Esketamine's label. DailyMed label · d81a6a79-a74a-44b7-822c-0dfa3036eaed · 2026-03-31
Q3
1047 registered trials of Esketamine — at which phases?
Registered studies posting no result
829 of 1047
1047 registered studies of Esketamine: 276 phase4, 235 na, 227 phase2, 161 phase3, 134 phase1, 49 na or unstated, 46 early phase1. CLINICALTRIALS_SNAPSHOT · 2026-09-01
"Recruitment was very slow."; 150 of 1047 registered studies
Show the evidence
Trial
NCT00252122
terminated; "Recruitment was very slow."
NCT00556387
withdrawn; "This study has been withdraw from the IRB. The PI has transferred to another university. The IND was transferred."
NCT00595530
terminated; "Lack of enrollment and patient interest in study"
NCT00618397
terminated; "Poor recruitement"
NCT00646087
withdrawn; "Pilot study determined that this study would not be feasible."
NCT00721110
terminated; "Futility"
14 further recorded trials
NCT00921765
terminated; "Problems with patient recruitment"
NCT00947791
terminated; "Change in available resources for study procedures"
NCT01017237
terminated; "Protocol proved to be ineffective for adequate sedation for third molar surgery."
NCT01106846
terminated; "Resources not available to complete."
NCT01126957
terminated; "Investigator left institution."
NCT01130909
terminated; "The benefit of halting the study to analyze the available data outweighs the benefit of delaying the analysis to include data from remaining treatment periods"
NCT01135758
terminated; "End of funding of study"
NCT01170247
terminated; "lack of enrollment"
NCT01244880
terminated; "See termination reason in detailed description."
NCT01260649
terminated; "lack of funding to cover staff salary (clinician and research coordinator)"
NCT01309581
terminated; "limited enrollment"
NCT01320475
terminated; "Difficulty of Recruitment"
NCT01371110
terminated; "no funding"
NCT01500018
withdrawn; "Sponsor decision to withdraw."
recorded 2026-09-01 · last checked 2026-09-04
Q5
Human studies of Esketamine used Group B: 1% Ketamine group — over how long?
studies of Esketamine used the recorded amount. ClinicalTrials.gov · 2026-09-01
20 recorded entries; human; injection; also "Group B: 1% Ketamine group", "ketamine 0.5 mg/kg", "Ketamine (0.5 mg/kg)"
Show the evidence
human
NCT01106846
Group B: 1% Ketamine group
NCT01535937
ketamine 0.5 mg/kg
NCT01690988
Ketamine (0.5 mg/kg)
NCT01740492
Ketamine 0.15mg/kg
NCT01740492
Ketamine 0.3mg/kg
NCT01825083
0.9 % normal saline group receives same volume as ketamine dose
14 more recorded rows
humanNCT01955135
ketalar, 50mg/ml
humanNCT01998958
Esketamine 14 mg
humanNCT01998958
Esketamine 28 mg
humanNCT01998958
Esketamine 56 mg
humanNCT01998958
Esketamine 84 mg
humanNCT02085577
(S)-(+)-Ketamine Hydrochloride Solution 25 mg/ml
humanNCT02199678
ketamine 25 mg
humanNCT02267980
injection; Ketamine (Ketalar) 50mg/mL injection
humanNCT02403687
Ketamine 10%
humanNCT02418702
0.2 mg/kg ketamine
humanNCT02674295
Esketamine 50 mg
humanNCT02674295
Esketamine 20 mg
humanNCT02682225
Esketamine 112 mg
humanNCT02909049
KETAMINE 50 mg/ml ATC N01AX03 Marketing Authorisation number 47034
recorded 2026-09-01 · last checked 2026-09-04
Q6
Esketamine's half-life is 2 to 4 hours — which schedules were studied?
2 to 4 hours, the half-life Esketamine's label states: "Elimination After C max was reached following intranasal administration, the decline in plasma esketamine concentrations was biphasic, with rapid decline for the initial 2 to 4 hours and a mean terminal half-life (t 1/2 ) that ranged from 7 to 12 hours." DailyMed label · d81a6a79-a74a-44b7-822c-0dfa3036eaed · 2026-03-31
bioavailability 48 %.
Show the evidence
half lifepharmacokinetics
2 to 4 hours; Elimination After C max was reached following intranasal administration, the decline in plasma esketamine concentrations was biphasic, with rapid decline for the initial 2 to 4 hours and a mean terminal half-life (t 1/2 ) that ranged from 7 to 12 hours.
bioavailabilitypharmacokinetics
48 %; Absorption The mean absolute bioavailability is approximately 48% following nasal spray administration.
metabolismpharmacokinetics
Metabolism Esketamine is primarily metabolized to noresketamine metabolite via cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 and to a lesser extent CYP2C9 and CYP2C19.
recorded 2026-03-31 · last checked 2026-09-04
Q7
Which running trial of Esketamine could settle lifespan?
NCT05437575 measures 24-hour mortality, reading out 2029-07.
1 open trial; n 994; "Prehospital Analgesia INtervention Trial (PAIN)"
Show the evidence
TrialNCT05437575
"Prehospital Analgesia INtervention Trial (PAIN)"; n 994; "24-hour mortality"; 2029-07
Q8
Which 316 trials of Esketamine posted no result?
Posted no result
316 of 316 completed trials
Registrations
NCT00625911, NCT02241278, NCT00163969, NCT00224588, NCT01017393 and NCT00300794, and 310 more
Completion dates
oldest 2002-03; newest 2024-08-30
Show the evidence
Trial
NCT00625911
2002-03
NCT02241278
2002-06
NCT00163969
2004-09
NCT00224588
2005-05
NCT01017393
2005-06
NCT00300794
2006-06
14 further recorded trials
NCT00137085
2006-08
NCT01947114
2006-08
NCT01439399
2007-07
NCT00556361
2007-11
NCT00587665
2007-12
NCT00440102
2008-03
NCT01070108
2009-01
NCT01146145
2009-01
NCT00614159
2009-06
NCT00858624
2009-07
NCT00484484
2009-09
NCT00690170
2009-09
NCT00847418
2009-10
NCT00579085
2009-11
Q9
At the median, Esketamine's trials enrolled 60 people — anything larger?
Median enrolment
60
Largest enrolment
50000
Registered trials counted
1045
Q10
What do 1682 spontaneous reports say about Esketamine — and not say?
These are reports people sent to a regulator. They do not show the medicine caused the reaction. Nobody counted how many people took the medicine and reported nothing. The same event can be reported more than once, and many reports are incomplete. News coverage, lawsuits and new warnings change how often people report. A count is not a rate and not a risk.
Esketamine appears in spontaneous reports to regulators. Across the 10 most-reported reaction terms, 1682 reaction mentions were counted: dissociation 318; sedation 255; anaphylactic shock 249; drug abuse 169. FAERS via Open Targets · CHEMBL2364609 · 2026-06-24
Show the evidence
dissociation
318
sedation
255
anaphylactic shock
249
drug abuse
169
hypotension
146
anxiety
124
4 more recorded rows
depression
111
anaphylactic reaction
110
suicidal ideation
105
agitation
95
recorded 2026-06-24 · last checked 2026-09-04
Q11
Which 10 reactions does Esketamine's label not list?
Metabolism Esketamine is primarily metabolized to noresketamine metabolite via cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 and to a lesser extent CYP2C9 and CYP2C19.
pharmacokinetics
Figure 2: Effect of Co-administered Drugs on the Pharmacokinetics of Esketamine Figure 3: Effect of Esketamine on the Pharmacokinetics of Co-Administered Drugs Figure 2 Figure 3 In Vitro Studies Enzyme Systems : Esketamine has modest induction effects on CYP2B6 and CYP3A4 in human hepatocytes.
pharmacokinetics
Esketamine and its major metabolites do not induce CYP1A2.
pharmacokinetics
Esketamine and its major circulating metabolites did not show inhibition potential against CYPs and UGTs, except for a weak reversible inhibition of noresketamine on CYP3A4.
pharmacokinetics
Transporter Systems : Esketamine is not a substrate of transporters P-glycoprotein (P-gp; multidrug resistance protein 1), breast cancer resistance protein (BCRP), or organic anion transporter (OATP) 1B1, or OATP1B3.
pharmacokinetics
Esketamine and its major circulating metabolites do not inhibit these transporters or multi-drug and toxin extrusion 1 (MATE1) and MATE2-K, or organic cation transporter 2 (OCT2), OAT1, or OAT3.
2 more recorded rows
Interaction statementclinical_pharmacology
Metabolism Esketamine is primarily metabolized to noresketamine metabolite via cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 and to a lesser extent CYP2C9 and CYP2C19.
Interaction statementclinical_pharmacology
Figure 2: Effect of Co-administered Drugs on the Pharmacokinetics of Esketamine Figure 3: Effect of Esketamine on the Pharmacokinetics of Co-Administered Drugs Figure 2 Figure 3 In Vitro Studies Enzyme Systems : Esketamine has modest induction effects on CYP2B6 and CYP3A4 in human hepatocytes.
ChEMBL 37 — CC BY-SA 3.0 Unported · ClinicalTrials.gov — US Government work · Open Targets 26.06 — CC0 · mixed register set; per-register licences in docs/specs/corpus-20k-sources.md · openFDA / DailyMed — US Government work
✗ required summary fields resolved: 4 required field(s) not terminal: Why people use it, Best-supported result, Biggest unanswered question, Human evidence
✓ public claims reviewed: 0 reviewed claim(s); drafts are never rendered
✓ source coverage passed: 6 source rows
✓ no critical contamination: no quarantine open
✓ canonical metadata passed: slug and display name present
✓ no raw internal fields: enforced by the copy-contract test over the rendered page
This is a record of evidence. It is not medical advice, and it does not say this substance suits you. Nothing here says any substance on RNAWiki is appropriate for a child.