RCT · 2026
Daily oral esketamine did not raise a brain growth protein more than placebo in depression
- Original title
- Serum brain-derived neurotrophic factor following oral esketamine in treatment-resistant depression: Results from a randomized placebo-controlled trial.
- Authors
- Massetti S, Smith-Apeldoorn SY, Veraart JKE, et al.
- Journal
- Journal of affective disorders, 2026
- Molecules
- Esketamine
- Conditions
- Treatment-resistant depression
- Participants
- 54
- Evidence grade
- Low
- Source
- Read the original paper
The question
Does six weeks of daily low-dose oral esketamine raise blood levels of BDNF, a protein linked to brain cell growth that has been proposed as a marker of antidepressant response?
What they did
Researchers used blood samples from a randomized, placebo-controlled trial of six weeks of oral esketamine (90 mg a day, taken as three 30 mg doses) in people with treatment-resistant depression, meaning depression that has not responded to previous treatments. Serum BDNF and depression severity were measured in 54 patients at the start, at the end of treatment, and after a four-week period off the drug. The original trial had already found no difference between esketamine and placebo on its main depression rating scale.
What they found
The change in BDNF levels did not differ significantly between the esketamine and placebo groups, either during treatment or during the washout period. BDNF rose over time in both groups regardless of which treatment they received (F(1,50) = 4.606, p = 0.037). Within the esketamine group, changes in BDNF were not related to changes in depression severity or to levels of ketamine breakdown products in the blood.
The fine print
This is a secondary analysis of blood samples from a trial that had already shown no benefit on its main depression measure, so there was no clinical response for the biomarker to track. The sample of 54 people is modest, follow-up ended four weeks after treatment, and blood BDNF is an indirect stand-in for what happens in the brain. The authors note it is unclear whether the dose and oral route simply never reached the level needed to affect brain plasticity. This summary is based on the abstract only.
What it means
In this trial, daily low-dose oral esketamine did not change a proposed blood marker of antidepressant action any more than placebo, which fits with its lack of effect on depression symptoms in the same study.
Evidence grade: Low. A secondary biomarker analysis of a modest-sized randomized placebo-controlled trial, so the blood-marker findings are exploratory rather than a primary test.
This summary is based on the study’s published abstract.