Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in…
Is a 4-point rating-scale difference likely to be noticeable for me, and how will we handle the dissociation window after each dose?
Reasonable evidence with real limitations. how we score evidence
Caveat on this rating: This was the single positive short-term pivotal trial; two sibling trials (TRANSFORM-1, TRANSFORM-3) missed their primary endpoints, which the approval package acknowledged. Sponsor employees authored the paper.
esketamine (Spravato) only — TRD 2019, monotherapy Jan 2025, REMS in force. Racemic ketamine is approved as an anesthetic; its psychiatric use is off-label.
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?
What it is FDA approved for
Read off the label. Trial duration and approval year are shown only where they were recorded — never inferred.
- Treatment-resistant depression (esketamine nasal spray, with oral antidepressant; monotherapy since Jan 2025) · approved 2019 · trials ran 4-week pivotal trial (TRANSFORM-2, day-28 endpoint)
- Depressive symptoms in MDD with acute suicidal ideation or behavior (esketamine, with oral antidepressant) · approved 2020
- Anesthesia (racemic ketamine only; all psychiatric use of racemic ketamine is off-label)
Source
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)
Top-tier peer-reviewed journal
Read the source: https://doi.org/10.1176/appi.ajp.2019.19020172
DOI: 10.1176/appi.ajp.2019.19020172
How this was scored
- Study design
- Randomised controlled trial
- Funding
- Funding not disclosed
- Published in
- Top-tier peer-reviewed journal
- Sample size
- 227
- Preregistered
- Yes
- Conflicts disclosed
- not recorded
- Independent of proponent
- No
- Retracted
- No
Read the full scoring rubric, including what it can't tell you.
Published August 19, 2026.
Where we put this study in context
Questions
How strong is the evidence behind this?
Resolv rates this source "moderate evidence". Reasonable evidence with real limitations. It scores 63 out of 100 on our published rubric. One caveat travels with that badge: This was the single positive short-term pivotal trial; two sibling trials (TRANSFORM-1, TRANSFORM-3) missed their primary endpoints, which the approval package acknowledged. Sponsor employees authored the paper. 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?
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). Published in: Top-tier peer-reviewed journal. DOI: 10.1176/appi.ajp.2019.19020172. 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: Randomised controlled trial. Funding: Funding not disclosed. The researchers were not independent of whoever benefits from the result. 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 esketamine, spravato FDA approved?
Yes — FDA approved for Treatment-resistant depression (esketamine nasal spray, with oral antidepressant; monotherapy since Jan 2025), Depressive symptoms in MDD with acute suicidal ideation or behavior (esketamine, with oral antidepressant), Anesthesia (racemic ketamine only; all psychiatric use of racemic ketamine is off-label). Approval is for a specific indication, not for everything the drug is prescribed for.
Where is this treatment in the FDA pipeline?
FDA approved. esketamine (Spravato) only — TRD 2019, monotherapy Jan 2025, REMS in force. Racemic ketamine is approved as an anesthetic; its psychiatric use is off-label.
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.