Esketamine in Teens: A Randomized Trial

This study will probably get reported as positive, but I’m not sure it is 

STUDY: Kosik-Gonzalez C et al, J of American Acad Child and Adolesc Psychiatry 2026

STUDY TYPE: Randomized controlled trial (phase 2b, double-blind, psychoactive-controlled)

FUNDING: Janssen Research & Development, LLC (a Johnson & Johnson company)

Background

Teens with major depression who are actively suicidal are almost never enrolled in antidepressant trials. Three earlier trials tested IV ketamine in teens with depression, but the results were not clearly significant when pooled together. This is the first trial (to my knowledge) to test esketamine (Spravato) in youth.

The Study

• 147 adolescents (ages 12 to 17) with major depression and imminent suicide risk, most moderately to extremely suicidal, were randomized to esketamine (28, 56, or 84 mg) or oral midazolam nasal spray twice weekly for four weeks.
• Everyone also received standard care: hospitalization, an oral antidepressant, and psychotherapy.
• The primary outcome was change in the Depression scale (CDRS-R) at 24 hours after the first dose.

Results

The individual esketamine doses did not separate from placebo on their own for depression, but did when pooled together.

Pooled 56 and 84 mg esketamine beat midazolam on the primary outcome, with about a 6-point greater drop in CDRS-R score (effect size 0.36, p=.037). Neither dose held up alone (56 mg, p=.072; 84 mg, p=.123), likely because each arm had only around 25 to 30 patients.

For suicidality, there was no significant difference, even when pooling the data. Esketamine suffered the same fate in adults. Although it was approved for depression with suicidality, it did not make a significant difference on suicidality in the registration trials. Instead, the FDA approved it based on its ability to treat depression in suicidal patients.

Roughly one in five patients in both esketamine and midazolam groups had self-injury during the trial, reflecting the population’s baseline risk rather than a drug effect.

Side Effects

Dizziness, nausea, dissociation, headache, altered taste, drowsiness, and vomiting were common, usually resolving within 90 minutes, similar to what’s seen in adults.

Limitations

Small size, possible unblinding. Concurrent treatments possibly obscured anti-suicide effects.

Practice Implications

1. The glass is half-empty.
2. Esketamine only met significance when pooled, and even then the p value was marginal. Also , a meta-analysis in teens was largely negative.