- Design
- randomised, placebo-controlled trial
- Population
- 173 analysed patients with preoperative anxiety undergoing major abdominal tumour surgery
- Primary outcome
- response at postoperative day 3 (≥50% fall in Hamilton Anxiety Rating Scale score)
- Effect
- 39.5% against 42.5%; risk ratio 0.93 (95% CI 0.65-1.33), P=0.81
One hundred and eighty patients who screened positive for preoperative anxiety before major abdominal tumour surgery were randomised to esketamine or placebo; 173 were analysed. The primary outcome was response at postoperative day 3, defined as a fall of at least half in the Hamilton Anxiety Rating Scale score.
Response occurred in 39.5% on esketamine and 42.5% on placebo (risk ratio 0.93, 95% CI 0.65-1.33, P=0.81). Hamilton scores at day 3 were the same (median 6 against 7; adjusted mean difference 0, 95% CI -2 to 1) and at day 30 (5 against 7; adjusted mean difference -1, -3 to 1). One secondary outcome did separate: depressive symptom scores at day 30 were lower on esketamine (median 5 against 6; adjusted mean difference -2, 95% CI -3 to -1, P=0.001).
That single positive secondary outcome is the part to handle carefully. It is consistent with what esketamine is known to do - it has an antidepressant effect - but it was one of several secondary endpoints in a trial that missed its primary, and a two-point median difference on a depression scale is at the edge of what a patient would notice. The clinically useful message is the negative one: a patient who is anxious before cancer surgery will not be made less anxious by adding esketamine to the anaesthetic, and the response rate of about 40% in the placebo arm shows how much of postoperative anxiety settles on its own.
- Do not add esketamine to an anaesthetic technique for the indication of preoperative or postoperative anxiety
- Screen for preoperative anxiety anyway - it identified a group in which 60% still had residual anxiety at day 3
- Where anxiety persists past the first postoperative week, assess it as you would any new presentation rather than attributing it to surgery
- Note the placebo arm: about two in five responded without the drug, which is the benchmark any agent has to beat
Why it matters
It removes a plausible off-label use of a drug that is increasingly available in theatre.
Don't overread it
The depression benefit at day 30 was a secondary endpoint in a trial that missed its primary outcome.
The statistics, in plain English
A risk ratio of 0.93 with a confidence interval of 0.65 to 1.33 spans benefit and harm and sits squarely on 1.0, so this is a clear null rather than a near miss. The day-30 depression difference survived where others did not, but a secondary endpoint in a trial that missed its primary is a finding to test next, not to act on - the more outcomes measured, the more likely one separates by chance.
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