Esketamine nasal spray added to an antidepressant: pooled results from six trials

The question

How well does intranasal esketamine, added to a standard oral antidepressant, work for depression that has not responded to previous treatments, and what are the harms?

What they did

Researchers searched the literature and combined randomized controlled trials that compared esketamine nasal spray plus an oral antidepressant against a placebo nasal spray plus the same oral antidepressant in people with treatment-resistant depression. From 1,518 records they included nine reports covering six separate trials with 1,836 participants. They analyzed the first roughly four weeks of treatment separately from longer maintenance trials, in which people who had already improved were randomly either kept on esketamine or switched off it. Depression was measured with the MADRS symptom scale and day-to-day functioning with the Sheehan Disability Scale.

What they found

In four short-term trials (937 people), esketamine lowered MADRS scores more than placebo at day 28 (mean difference -2.99, 95% CI -5.10 to -0.89), with a difference already visible at day 2 (-3.25, 95% CI -4.65 to -1.85). Response was more likely (risk ratio 1.44) as was remission (risk ratio 1.52), which the authors translate to about 154 extra responders and 106 extra remitters per 1,000 patients. Functioning also improved (Sheehan difference -1.70). In two maintenance trials (899 people), staying on esketamine roughly halved the risk of relapse (hazard ratio 0.51, 95% CI 0.42 to 0.62). Harms were higher in the acute phase: any side effect (RR 1.37), stopping treatment because of side effects (RR 2.68), dissociation, a feeling of detachment from oneself or one’s surroundings (RR 7.33), and raised blood pressure (RR 3.96); during maintenance, overall side-effect rates were similar between groups (RR 1.07, 95% CI 0.99 to 1.17).

The fine print

Only six trials were pooled, and the short-term results varied moderately between them (I²=48.5%). Dissociation and blood pressure changes can reveal who received the active drug, which can inflate apparent benefit. The maintenance findings apply only to people who had already responded or remitted, a selected group. Average symptom gains were modest, and this summary is based on the abstract alone.

What it means

Pooled trial evidence suggests esketamine nasal spray added to an antidepressant gives a rapid but modest short-term improvement in treatment-resistant depression and lowers relapse risk in people who have already improved, at the cost of more short-term side effects that need medical supervision.

Evidence grade: Moderate. A meta-analysis of randomized placebo-controlled trials, but it pools only six trials, shows moderate variation between the short-term studies, and esketamine’s noticeable side effects make true blinding difficult.

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