Esketamine's effect on suicidal thoughts appears tied to its effect on depression

The question

Does esketamine reduce suicidal thinking in its own right, or does that reduction simply follow from the improvement in depression?

What they did

This was a two-centre observational study of 261 adults with moderate-to-severe treatment-resistant depression, meaning depression that had not responded to previous treatments. Participants received eight sessions of intranasal esketamine over four weeks. Before each session, clinicians rated symptoms using the Montgomery-Asberg Depression Rating Scale, separating the nine general depression items (MADRS-D) from the single item that measures suicidal thoughts (MADRS-S). The researchers then tested whether changes in suicidal thinking held up statistically once changes in depression were accounted for.

What they found

Both depression scores and suicidal ideation scores improved over the course of treatment (all p < .001). When the analysis adjusted for suicidal ideation, the improvement in depression remained statistically significant (all p < .001). But when the analysis adjusted for depression scores, the reduction in suicidal ideation was no longer significant (all p > .949). The authors conclude that the apparent anti-suicidal effect does not persist once the antidepressant effect is taken into account.

The fine print

There was no placebo or comparison group, so improvements cannot be attributed to esketamine alone. Suicidal ideation was measured with a single rating-scale item, which is a crude measure and does not capture suicidal behaviour. Follow-up covered only the four-week treatment period, and participants were drawn from two specialist hospital centres, so results may not generalize. This summary is based on the abstract only.

What it means

In this group of patients, the drop in suicidal thoughts during esketamine treatment tracked closely with the drop in overall depression, rather than appearing to be a separate effect. That distinction matters for how esketamine is approved and described, though a single observational study cannot settle the question.

Evidence grade: Low. An observational study with no control or placebo group and a statistical adjustment analysis, so it cannot establish cause and effect.

This summary is based on the study’s published abstract.