How the FDA approved esketamine: two of four phase 3 studies positive, one a withdrawal study, and an unblinding worry
The FDA 2019 review: esketamine was approved on one positive four-week trial plus a randomised withdrawal study. Two other phase 3 trials were not positive, and reviewers could not rule out that unblinding swayed the withdrawal result.
We have not finished checking this source. No judgement either way. how we score evidence
Caveat on this rating: This is the regulator that approved the drug, describing its own doubts and why it approved anyway. It cannot say whether the placebo relapses were withdrawal, unblinding or true relapse; it says the reviewers could not tell.
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?
Source
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)
Regulator or national health body
Read the source: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211243Orig1s000SumR.pdf
How this was scored
- Study design
- Regulatory safety determination
- Funding
- not recorded
- Published in
- Regulator or national health body
- Sample size
- not recorded
- Preregistered
- not recorded
- Conflicts disclosed
- not recorded
- Independent of proponent
- not recorded
- Retracted
- No
We have not finished checking this source, so there is no scoring to show yet. “We have not checked this yet” and “this is disputed” are different statements, so no scored band is shown rather than a low one.
Read the full scoring rubric, including what it can't tell you.
Published October 2, 2026.
Questions
How strong is the evidence behind this?
veisund rates this source "not yet assessed". We have not finished checking this source. No judgement either way. One caveat travels with that badge: This is the regulator that approved the drug, describing its own doubts and why it approved anyway. It cannot say whether the placebo relapses were withdrawal, unblinding or true relapse; it says the reviewers could not tell. The score is calculated from recorded facts about the source — study design, funding, publication venue, sample size, preregistration — not typed in by an editor.
What is the source for this?
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). Published in: Regulator or national health body. The full source is linked on this page so you can read it yourself.
Who paid for this research, and does that matter?
Study design: Regulatory safety determination. Funding: not recorded. Independence from the proponent is not recorded. Industry sponsorship is one of the most reliably measured biases in medicine, which is why funding carries real weight in the score rather than sitting in a footnote.
Is this medical advice?
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.