esketamine (Spravato)

How long the esketamine trials actually ran

What esketamine is FDA approved for, and the trials behind it

Trials

1 short-term placebo-controlled trial, plus a maintenance study

Duration

4 weeks

Participants

114 on esketamine vs 109 on placebo spray

Compared against

Placebo nasal spray; both arms on a newly initiated oral antidepressant

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).

Verbatim from the esketamine FDA label, Clinical Studies section, effective March 31, 2026 — read the full label on DailyMed.

Side effects of esketamine in the approval trials

• Dissociation (41% vs 9% on placebo spray)
• Dizziness (29% vs 8%)
• Nausea (28% vs 9%)
• Sedation (23% vs 9%)
• Vertigo (23% vs 3%)
• Headache (20% vs 17%)
• Dysgeusia (19% vs 14%)
• Hypoesthesia (18% vs 2%)
• Anxiety (13% vs 6%)
• Lethargy (11% vs 5%)
• Blood pressure increased (10% vs 3%)
• Vomiting (9% vs 2%)

The most commonly observed adverse reactions in patients treated with SPRAVATO plus oral AD (incidence ≥5% and at least twice that of placebo nasal spray plus oral AD) were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, blood pressure increased, vomiting, and feeling drunk.

From the esketamine FDA label, Adverse Reactions section, effective March 31, 2026 — DailyMed.

More from the esketamine label: drug abuse and dependence

• Schedule III controlled substance

  Esketamine, the (S)-enantiomer of ketamine, is a Schedule III controlled substance under the Controlled Substances Act. In a cross-over abuse-potential study in 34 recreational polydrug users, drug-liking and take-drug-again scores for single intranasal doses were similar to intravenous ketamine and greater than placebo.

  FDA label, Drug Abuse and Dependence section.

• Dependence and tolerance

  No withdrawal symptoms were captured up to 4 weeks after stopping esketamine, but physical dependence, withdrawal symptoms and tolerance have been reported with prolonged use of frequently taken large doses of ketamine, and the label says similar effects would be likely or expected if esketamine were similarly abused. It advises monitoring patients for signs of physical dependence on discontinuation.

  FDA label, Drug Abuse and Dependence section.

• Dispensed only through a restricted program

  Esketamine is available only through the SPRAVATO REMS: it is dispensed and administered in certified healthcare settings, self-administered under the direct observation of a healthcare provider, and patients are monitored by a healthcare provider for at least 2 hours after each dose.

  FDA label, Warnings and Precautions section.

What people report to the FDA about esketamine

17,728

reports mentioning esketamine, all time

12,338

filed as serious (a report-level flag covering every drug and outcome in the report)

filed as serious. That flag covers the whole report, and one report can name more than one drug and more than one outcome.

Source: FDA Adverse Event Reporting System (FAERS), via openFDA, openFDA dataset refreshed 2026-07-30 (the refresh date of the query endpoint, not the date reports run through).

Drug interactions listed on the esketamine label

FDA label for esketamine, effective March 31, 2026 — DailyMed.

The esketamine approval, step by step

1. 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.

2. 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

3. Step 3

   What was added after it was on the market

   Which warnings arrived only after millions of people were already taking it?

   • How the FDA approved esketamine: two of four phase 3 studies positive, one a withdrawal study, and an unblinding worry

     The regulator's own account of what esketamine's approval rested on, read beside the relapse trial (SUSTAIN-1) it discusses.

     What the FDA wrote

     The approval was based on "two positive adequate and well-controlled studies": Study 3002, a four-week flexible-dose trial, and Study 3003, "a randomized, double-blind, controlled, withdrawal study" (published as SUSTAIN-1). The review says "Studies 3001 and 3005 were not positive studies." In 3001 the 84 mg dose "did not separate from placebo". Study 3005, in people 65 and over, was called a "near miss". The review adds that esketamine studies lasted only four weeks, while antidepressant trials are "typically 6 to 8 weeks".

     On the withdrawal study

     People who had already improved on esketamine for 16 weeks were randomised to keep it or switch to placebo. The FDA notes this is "an enriched population" that differs "from the patient population that would ordinarily receive a prescription". Relapse in the placebo arm rose fast in the first 25 to 30 days, "qualitatively different" from withdrawal studies of oral antidepressants. The clinical team "was concerned that unblinding (i.e., patients familiar with dissociative effects of esketamine would know if they were randomized to placebo) may have biased the study". Their analyses "were unable to determine conclusively whether unblinding swayed the study results." One site in Poland "was noted to have driven the primary endpoint efficacy results", with every placebo patient there relapsing; inspection found no conduct problems.

     The other direction

     The FDA still concluded the evidence met the legal standard, and it gave the reasons. In the withdrawal study stable remitters on esketamine took longer to relapse (hazard ratio 0.49; 95% CI 0.29 to 0.83), and stable responders too (0.30; 0.16 to 0.55). Study 3001's size of effect was in the usual antidepressant range, and people in these trials were sicker than in earlier antidepressant trials. The advisory committee voted 14 to 2, with 1 abstention, that effectiveness was shown.

     What this does not show

     It does not settle whether esketamine works for any one person. Nothing here says anyone should start, continue or stop it; that is a decision with a prescriber.

     Worth asking

     If esketamine is offered to me, what is the evidence for the first four weeks, and what is known about stopping it later?

     Summary Review, NDA 211243 (esketamine nasal spray, Spravato), Center for Drug Evaluation and Research — Fischer BA, Farchione TR (US Food and Drug Administration, CDER) (2019)

   • The esketamine label: sedation in up to 61 percent, dissociation in up to 84 percent, more with sedatives or alcohol

     7 years after approval

     Esketamine is the prescription cousin of street ketamine, and its label is the closest thing to a regulator's account of what ketamine does with other drugs.

     Significant findings

     SPRAVATO prescribing information (Janssen, August 2026), Drug Interactions 7.1: "Concomitant use with CNS depressants (e.g., benzodiazepines, opioids, alcohol) may increase sedation. Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants."

     What the drug does alone, from the Warnings: "In clinical trials, 48% to 61% of SPRAVATO-treated patients developed sedation"; "61% to 84% of SPRAVATO-treated patients developed dissociative or perceptual changes"; "In post marketing experience, respiratory depression was observed with the use of SPRAVATO. In addition, there were rare reports of respiratory arrest". On blood pressure: "Approximately 3% to 19% of SPRAVATO-treated patients and 1% to 4% of placebo-treated patients experienced an increase of greater than or equal to 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration". Because of these, patients "must be monitored by a healthcare provider for at least 2 hours at each treatment session".

     The label also records what long-term misuse does: "Cases of ulcerative or interstitial cystitis have been reported in individuals with long-term off-label use or misuse/abuse of ketamine."

     Worth asking

     A clinic gives esketamine under two hours of observation with a blood pressure cuff on. Street ketamine is the same molecule family taken with none of that, often with alcohol or a benzodiazepine, which is the combination the label says deepens sedation and, in the boxed warning, can depress breathing. The bladder line is the one recreational users rarely hear. If you use ketamine and take a benzodiazepine, an opioid, or drink, the label's own monitoring rules are the measure of the risk you are taking without them.

     SPRAVATO (esketamine) nasal spray: FDA-approved prescribing information, Boxed Warning, Warnings and Precautions 5.1 to 5.3, 5.7, 5.10, Drug Interactions 7.1 — Janssen Pharmaceuticals, Inc.; US Food and Drug Administration (2026)

4. Step 4

   What independent research has found since

   What has been learned by people who were not selling it?

   • Higher benzodiazepine doses went with non-response to ketamine for depression, above 8 mg diazepam-equivalent

     1 year after approval

     Ketamine, from a clinic or from the street, works on the same brain systems benzodiazepines quiet. This study asked whether the sedative blunts the antidepressant.

     Significant findings

     Andrashko and colleagues (Frontiers in Psychiatry, 2020) analysed 47 patients with major depression who had not responded to at least one antidepressant and received a single infusion of racemic ketamine, 0.54 mg per kilogram, on top of their existing medication. "Thirteen patients (28%) reached ≥ 50% reduction in MADRS within one week after ketamine administration. Nineteen (40%) patients took concomitant benzodiazepines on a daily basis."

     "The doses of BZDs were significantly higher in nonresponders (p=0.007). ROC analysis distinguished responders from nonresponders by a criterion of >8mg of diazepam equivalent dose (DZ equivalent) with a sensitivity of 80% and a specificity of 85% (p<0.001)." Patients above that dose had "a significantly worse outcome" on day 3 and day 7.

     "The results of the study indicate that concomitant benzodiazepine treatment in higher doses may attenuate ketamine's antidepressant effect." A 2015 letter by Frye, Blier and Tye in the Journal of Clinical Psychopharmacology, read for this wave, reported the same pattern under the title "Concomitant benzodiazepine use attenuates ketamine response".

     Worth asking

     Forty seven patients and a retrospective split, so the cut-off is a hypothesis, not a rule. The direction is consistent across the two reports, and it matters in both settings: a person paying for ketamine treatment while on a moderate benzodiazepine dose may be paying for less effect, and a person using street ketamine on top of a benzodiazepine is combining two sedatives, which the esketamine label in this wave addresses directly. If ketamine treatment is on the table, the question for the clinic is what your benzodiazepine dose is in diazepam-equivalents and whether that changes the plan. Any change to the benzodiazepine is the prescriber's, with a taper; the same drugs cause dangerous withdrawal if stopped abruptly.

     The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication — Andrashko V, Novak T, Brunovsky M, Klirova M, Sos P, Horacek J (2020)

   • 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?

     Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis — Bahji A, et al. (2021)

   • 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 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 — Popova V, et al. (2019)

   • 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?

     Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial — Daly EJ, et al. (2019)

5. 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?