Esketamine side effects in treatment-resistant depression rise with higher doses

The question

How common are side effects from esketamine in people with depression that has not responded to other treatments, and do they get worse at higher doses?

What they did

Researchers searched six research databases (in English and Chinese) up to March 2025 for randomized controlled trials of esketamine in treatment-resistant depression. Nine trials with 1,449 patients were combined. Doses ranged from 28 to 84 mg as a nasal spray and 0.20 to 0.40 mg per kilogram of body weight by intravenous injection. They compared side effect rates, dropouts due to side effects, and response or remission against control groups, and looked separately at higher versus lower doses, route of delivery, and studies in Mainland China versus international multi-region trials.

What they found

Esketamine raised the risk of nine side effects compared with controls, including nausea, dissociation (a feeling of detachment from one’s body or surroundings), dizziness, vertigo, raised blood pressure and sleepiness. Risks tracked with dose: in the higher-dose group (56 mg or more, or 0.40 mg/kg) the relative risk of nausea was 3.72 versus 1.69 in the lower-dose group, and for dissociation it was 10.65 versus 3.27. Patients in international multi-region trials had higher risks of nausea, sleepiness and headache than those in Mainland China trials. Esketamine improved the clinical response rate (relative risk 1.94) but also raised stopping treatment because of side effects by 2.22-fold (P = 0.025).

The fine print

Nine trials and 1,449 patients is a modest pool for splitting into dose, route and region subgroups, so those comparisons are less reliable than the overall results. The abstract does not report confidence intervals, follow-up length, or how much the trials varied from one another. Regional differences could reflect how side effects were recorded rather than true biological differences. This summary is based on the abstract alone.

What it means

Esketamine appears to help some people whose depression has not responded to other treatments, but side effects such as nausea and dissociation become markedly more likely at higher doses, and more people stop treatment because of them.

Evidence grade: Moderate. A pre-registered meta-analysis pooling nine randomized controlled trials, but the trials differ in dose, route and region, which limits how precisely the pooled numbers apply.

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