Medication approval journey
esketamine (Spravato)
Approved for Treatment-resistant depression, with an oral antidepressant
Before changing anything
Low risk from stopping, but still worth planning
Esketamine is given in a certified clinic under federal safety monitoring, not taken home, so abrupt self-discontinuation is not the hazard it is for other drugs in this library. The risk when treatment ends is relapse of the depression being treated — plan the ending with your prescriber the same way the beginning was planned, including what gets monitored and what the fallback is.
How long the trials actually ran
The longest trial behind the esketamine approval ran 4 weeks.
The gap between how long the trials ran and how long people actually take these medications is the single most important thing on this page. It is not evidence that longer use is unsafe or ineffective. It is evidence that longer use was not what got tested.
The boxed warning
The strongest warning the FDA puts on a label, reproduced word for word — not our summary of it.
WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS WARNING: SEDATION; DISSOCIATION; RESPIRATORY DEPRESSION; ABUSE AND MISUSE; and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Risk for sedation, dissociation, and respiratory depression after administration. Monitor patients for at least two hours after administration. ( 5.1 , 5.2 , 5.3 ) Potential for abuse and misuse. Consider the risks and benefits of prescribing SPRAVATO prior to using in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse. ( 5.4 ) SPRAVATO is only available through a restricted program called the SPRAVATO REMS. ( 5.5 ) Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. SPRAVATO is not approved for use in pediatric patients. ( 5.6 ) Sedation Patients are at risk for sedation after administration of SPRAVATO [see Warnings and Precautions (5.1) ]. Dissociation Patients are at risk for dissociative or perceptual changes after administration of SPRAVATO [see Warnings and Precautions (5.2) ]. Respiratory Depression Respiratory depression has been observed in postmarketing experience [see Warnings and Precautions (5.3) ] . Because of the risks of sedation, dissociation, and respiratory depression, patients must be monitored for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the healthcare setting [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Abuse and Misuse SPRAVATO has the potential to be abused and misused. Consider the risks and benefits of prescribing SPRAVATO prior to use in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse [see Warnings and Precautions (5.4) ] . Because of the risks of serious adverse outcomes resulting from sedation, dissociation, respiratory depression, abuse and misuse, SPRAVATO is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS [see Warnings and Precautions (5.5) ] . Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. SPRAVATO is not approved for use in pediatric patients [see Warnings and Precautions (5.6) ] .
FDA label effective March 31, 2026 — read the full label on DailyMed
What people report to the FDA about esketamine
Read this before the numbers.
Anyone can file an adverse event report — patients, doctors, manufacturers — and nobody verifies that the drug caused what was reported. There is no denominator: tens of millions of prescriptions generate reports at an unknowable rate, and reporting rises with news coverage, not necessarily with harm. Counts below are report volumes, not rates, and cannot be compared between drugs. The FDA itself says not to use this data to make medical decisions — we show it because you deserve to see what is in the public record, with its limits stated plainly.
- 17,728
- reports mentioning esketamine, all time
- 12,338
- filed as serious (a report-level flag covering every drug and outcome in the report)
Most-reported reactions
- Dissociation3,733
- Sedation2,706
- Suicidal ideation1,351
- Drug ineffective1,082
- Nausea957
- Depression873
- Hypertension844
- Product dose omission issue792
- Hospitalisation787
- Anxiety738
“Drug ineffective” ranking this high is worth noticing: a report of not being helped counts as an adverse event too, and people file them in large numbers.
Source: FDA Adverse Event Reporting System (FAERS), via openFDA, data through 2026-07-30.
Known interactions, from the label
The FDA label’s interactions section, verbatim. A pharmacist checking your actual medication list beats any published list — including this one.
Read the label’s interactions section
7 DRUG INTERACTIONS
7.1 Central Nervous System Depressants Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation [see Warnings and Precautions (5.1) ] . Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants.
7.2 Psychostimulants Concomitant use with psychostimulants (e.g., amphetamines, methylphenidate, modafinil, armodafinil) may increase blood pressure [see Warnings and Precautions (5.7) ] . Closely monitor blood pressure with concomitant use of SPRAVATO with psychostimulants.
7.3 Monoamine Oxidase Inhibitors (MAOIs) Concomitant use with monoamine oxidase inhibitors (MAOIs) may increase blood pressure [see Warnings and Precautions (5.7) ] . Closely monitor blood pressure with concomitant use of SPRAVATO with MAOIs.
FDA label for esketamine, effective March 31, 2026 — DailyMed.
The approval, step by step
Step 1
What the approval was actually based on
Which studies did the FDA rely on, how long did they run, and who was in them?
SPRAVATO was evaluated in a randomized, placebo-controlled, double-blind, multicenter, short-term (4-week), Phase 3 study (Study 1; NCT02418585) in adult patients 18 to <65 years old with treatment-resistant depression (TRD).
FDA-approved labelling, 14 CLINICAL STUDIES — read the label on DailyMed
Our reading
A four-week acute trial plus a longer randomised-withdrawal maintenance study — the same design caveat as sertraline's entry applies: withdrawing a drug from people doing well on it measures relapse-or-withdrawal, not fresh benefit. Two structural facts distinguish this journey from everything else here. It was the first genuinely new antidepressant mechanism approved in decades, on priority review. And it cannot be taken home: every dose is administered in a certified clinic under a federal REMS, with two hours of post-dose monitoring — a set of controls that is simultaneously a safety architecture and a statement about the drug it wraps.
Step 2
The approval
When was it approved, under what application, and by whose review?
- Approved
- March 5, 2019
- Application
- NDA211243
- Review
- PRIORITY
- Original sponsor
- Janssen Pharmaceuticals
- Holds it now
- Janssen Pharmaceuticals
- Label submissions since
- 18
Source: openFDA Drugs@FDA, original application ORIG-1
Step 3
What was added after it was on the market
Which warnings arrived only after millions of people were already taking it?
We have not recorded a post-approval change to the esketamine label. That is the state of our record, not a finding that nothing was ever added.
Step 4
What independent research has found since
What has been learned by people who were not selling it?
Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis
2 years after approval
Across 24 randomized trials (1,877 participants), both ketamine forms outperformed placebo for unipolar/bipolar depression, with indirect comparisons suggesting larger response/remission effects for IV racemic ketamine than intranasal esketamine — a hypothesis-generating, not head-to-head, comparison.
Worth asking
Should IV racemic ketamine (off-label, unreimbursed) be considered against approved esketamine in my case, and on what evidence?
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in…
In 227 adults with treatment-resistant depression (TRANSFORM-2), esketamine plus a new oral antidepressant beat placebo spray plus antidepressant by 4.0 MADRS points at day 28 — statistically significant but a modest absolute difference, with dissociation, nausea, vertigo and dizziness markedly more common on esketamine.
Worth asking
Is a 4-point rating-scale difference likely to be noticeable for me, and how will we handle the dissociation window after each dose?
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With…
Among 297 patients stabilized on esketamine (SUSTAIN-1), continuing esketamine plus antidepressant halved relapse risk vs switching to placebo spray (relapse 27% vs 45% in stable remitters; NNT 6) — evidence for maintenance benefit, and also that stopping esketamine carries a real relapse risk.
Worth asking
If this works for me, what is the plan and timeline for ever stopping it?
Step 5
What still is not known
Which questions you might reasonably have has nobody answered yet?
- Approved with an oral antidepressant, not instead of one. Is that how it is being used?
- The maintenance evidence is a randomised-withdrawal design. What does it actually establish about year two?
- Every dose requires clinic administration and two hours of monitoring. What do those requirements say about what stopping unsupervised would mean?
Deciding about esketamine?
- 12 questions to ask before starting a psychiatric medication — each with the study behind it
- Already on it? The 10-question annual review — including the honest case for staying
- How long every drug here was tested before approval — one chart, all medications
Open esketamine (Spravato) in Resolv
The app has the full approval journey, the resources behind it, and people working through the same questions.
