If you are having thoughts of harming yourself, please contact your local emergency services or a crisis helpline now. This article summarises a research result and is not a source of urgent help.
Esketamine attracts attention because it works fast. Conventional antidepressants take weeks, which is a serious problem when someone is in hospital because they are at immediate risk. A phase 2 trial published in the Journal of the American Academy of Child and Adolescent Psychiatry tested whether that speed translates to adolescents in exactly that position.
The answer is more qualified than the drug’s reputation suggests, and the qualification is the interesting part. [pubmed-depression-jul13-2026-source]
What the researchers did
One hundred and forty-seven adolescents aged 12 to 17, all with major depressive disorder and all judged to be at imminent risk of suicide, were randomly assigned to esketamine nasal spray at one of three doses, or to oral midazolam, twice weekly for four weeks.
Two design choices matter for reading the result.
Everyone received full standard care. Initial hospitalisation, an oral antidepressant, and evidence-based psychotherapy, in every group. The trial was asking what esketamine adds to proper treatment, not whether it beats nothing.
The comparison was an active drug. Midazolam is a sedative, not an antidepressant, chosen because it produces noticeable effects of its own. With an inert placebo, participants given a dissociative drug would quickly work out which group they were in, and the blinding would collapse. This is a harder test, and effects measured against it are correspondingly more credible when they appear.
The main measurement was depression score 24 hours after the first dose. Around 95% of participants were rated moderately to extremely suicidal at enrolment.
What they found on depression
The two higher doses, combined into one group, produced a larger drop in depression score at 24 hours than midazolam. That was the trial’s stated goal and it was met.
Read one level down, though, and it is thinner than it sounds. Neither the 56mg dose nor the 84mg dose was significant when analysed on its own. The result exists because the two were pooled.
Author-drawn illustration of results reported by Kosik-Gonzalez and colleagues (2025). The second view shows the weakest advantage each analysis remains consistent with; a bar at zero means the analysis could not rule out no advantage at all.
Switch between the two views and the situation becomes clear. All three estimates are nearly identical: around six points. What separates them is precision. Each dose on its own leaves open the possibility of no benefit at all, and pooling them doubles the number of people in the comparison, which narrows the range just far enough to exclude zero.
That is a legitimate, pre-specified way to analyse a trial. It also means this study did not establish which dose to give, and that its central finding rests on a range whose lower end sits a third of a point above nothing.
What they found on suicidality
This is the part that deserves the headline.
Severity of suicidality improved in all four groups, by broadly similar amounts, with no meaningful separation between any esketamine dose and midazolam.
Everyone got better. That is genuinely good news for the adolescents in the trial, and it is what you would hope for from hospitalisation plus an antidepressant plus psychotherapy. But it is not evidence that esketamine reduced suicidality, because the group that did not receive it improved just as much.
Given that imminent suicide risk was the enrolment criterion, a trial that separates the groups on depression scores and not on suicidality has answered a narrower question than the one its framing implies.
The adverse events
Reported in at least a fifth of esketamine participants: dizziness, nausea, dissociation, headache, a bitter taste, sleepiness, vomiting, reduced sensation, and intentional self-injury.
The last one cannot be cleanly attributed to the drug. In a group selected for imminent suicide risk, self-injury has a high background rate whatever the treatment. But it appears on the list, and a summary that reported the efficacy result without it would be selecting.
How to read this overall
As an early-stage result that justifies further work, not as a settled finding.
Phase 2 trials exist to decide whether a larger, more definitive study is worth running. This one suggests esketamine may add something to standard care for adolescent depression in a crisis, at a speed conventional drugs cannot match, and that the size of that addition is not yet pinned down. It gives no support to the idea that it reduces suicidality faster than good hospital care does.
The other thing worth taking from it: every group improved substantially. When the full package of hospitalisation, medication and therapy is delivered properly, adolescents in this position get better. That is the least surprising finding here and probably the most useful one.
If this is your situation now
If you or a young person you know is having thoughts of suicide, contact your local emergency services or a crisis helpline immediately. If depression in a teenager is the wider concern, our depression overview sets out the treatments with established evidence and how to get an assessment.
The source
These findings are drawn from “Effect of Esketamine on Depressive Symptoms in Adolescents With Major Depressive Disorder at Imminent Suicide Risk: A Randomized Psychoactive-Controlled Study” (Kosik-Gonzalez C, Fu DJ, Chen LN, et al., 2025), published in the Journal of the American Academy of Child and Adolescent Psychiatry. Read the full study on PubMed.