Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis
Should IV racemic ketamine (off-label, unreimbursed) be considered against approved esketamine in my case, and on what evidence?
Well-supported by good-quality research. how we score evidence
Caveat on this rating: The racemic-vs-esketamine difference rests on indirect comparison across trials with different designs and populations; one coauthor (Zarate/NIMH) is an inventor on ketamine-related patents. An erratum was issued in 2021 (checked: not a retraction).
esketamine (Spravato) only — TRD 2019, monotherapy Jan 2025, REMS in force. Racemic ketamine is approved as an anesthetic; its psychiatric use is off-label.
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?
Source
Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis — Bahji A, et al. (2021)
Reputable peer-reviewed journal
Read the source: https://doi.org/10.1016/j.jad.2020.09.071
DOI: 10.1016/j.jad.2020.09.071
How this was scored
- Study design
- Meta-analysis of randomised trials
- Funding
- No external funding
- Published in
- Reputable peer-reviewed journal
- Sample size
- 1,877
- Preregistered
- No
- Conflicts disclosed
- not recorded
- Independent of proponent
- not recorded
- 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 "strong evidence". Well-supported by good-quality research. It scores 80 out of 100 on our published rubric. One caveat travels with that badge: The racemic-vs-esketamine difference rests on indirect comparison across trials with different designs and populations; one coauthor (Zarate/NIMH) is an inventor on ketamine-related patents. An erratum was issued in 2021 (checked: not a retraction). 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?
Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis — Bahji A, et al. (2021). Published in: Reputable peer-reviewed journal. DOI: 10.1016/j.jad.2020.09.071. 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: Meta-analysis of randomised trials. Funding: No external funding. 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.