Re-analysis of esketamine trials finds a small benefit for treatment-resistant depression

The question

Does intranasal esketamine actually help people with depression that has not responded to other treatments, and how safe is it? The authors re-examined the trial data that regulators used to approve it.

What they did

Researchers ran a systematic review and an individual patient data meta-analysis, meaning they obtained the raw, person-by-person results from the original trials rather than only the published summaries. They included double-blind, randomized, placebo-controlled trials of intranasal esketamine for treatment-resistant depression, obtaining data through the Yale Open Data Access Project. They re-analyzed data from 7 trials including 1,505 patients, and judged the size of any benefit against the 6.5-point improvement on the Montgomery-Asberg Depression Rating Scale (MADRS, a clinician-rated depression score) that the original trials were designed around.

What they found

In five trials of esketamine added to an antidepressant, esketamine lowered MADRS depression scores at 4 weeks by an average of 2.94 points more than placebo (95% confidence interval -5.39 to -0.48), which is less than half the 6.5-point threshold used as the mark of clinical significance. One continuation trial found a lower risk of relapse (hazard ratio 0.38, 95% CI 0.26-0.57). A single monotherapy trial, for which only summary data were available, showed a larger difference of 6.32 points (95% CI -8.62 to -4.03), but the authors flagged concerns about selection bias and unblinding. Esketamine increased sedation (risk ratio 3.70), dissociation, a sense of detachment from oneself or one’s surroundings (risk ratio 2.36), and adverse events overall (incidence rate ratio 3.91), with no increase in serious adverse events (incidence rate ratio 1.35, 95% CI 0.54-3.40). Age and level of treatment resistance did not change the size of the effect, and most patients had lower-stage treatment resistance.

The fine print

The analysis depends on the original trials, some of which had blinding problems: esketamine’s noticeable effects can reveal who received it. Data privacy rules meant the authors could not address the FDA’s concerns about one study centre in the continuation trial, and the monotherapy trial contributed summary data only. Most included patients had lower-stage treatment resistance, so results may not apply to more severe cases, and this summary is based on the abstract alone.

What it means

Pooling the raw trial data suggests esketamine plus an antidepressant works better than placebo, but the average improvement was small and smaller than the benchmark the trials themselves set, while side effects such as sedation and dissociation were clearly more common.

Evidence grade: Moderate. A meta-analysis pooling individual patient data from seven double-blind, placebo-controlled trials, but the authors rated certainty as moderate and flagged possible unblinding and selection bias in some trials.

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