Serum brain-derived neurotrophic factor following oral esketamine in treatment-resistant depression: Results from a randomized placebo-controlled trial

Abstract

Background Ketamine and its enantiomer esketamine are efficacious in 30-35% of the patients with treatment-resistant depression (TRD). Increased serum brain-derived neurotrophic factor (BDNF) following treatment has been proposed as a potential biomarker of antidepressant response. This is based on studies evaluating single intravenous ketamine treatment. BDNF expression at different treatment schedules remains unclear. Methods This study investigated the effects of daily, low-dose, oral (PO) esketamine on serum BDNF levels in TRD. Biomaterials were obtained from a randomized, placebo-controlled trial investigating six-week PO esketamine treatment (90 mg/day, three 30 mg intakes) that found no difference between conditions on the primary outcome (Hamilton Depression Rating Scale). Depression severity and serum BDNF levels were assessed in 54 patients at baseline, end of treatment, and after a four-week washout period. Repeated measures analyses of variance (ANOVA) were conducted to test the effect of treatment on depression severity and BDNF. Pearson's correlation analysis evaluated the association between changes in depression severity, ketamine metabolites and BDNF. Results The change in BDNF levels during treatment did not significantly differ between the esketamine and placebo group during treatment or washout. An increase in BDNF (F(1,50) = 4.606, p = 0.037) was found irrespective of treatment condition. In the esketamine arm, BDNF changes did not correlate with changes in depression severity, nor with metabolites levels. Conclusion Repeated, low-dose, PO esketamine did not increase serum BDNF relative to placebo. While consistent with its limited clinical efficacy, it remains uncertain whether this reflects an unreached pharmacological threshold to engage synaptic plasticity.

Abstract of "Serum brain-derived neurotrophic factor following oral esketamine in treatment-resistant depression: Results from a randomized placebo-controlled trial" by Massetti S, Smith-Apeldoorn SY, Veraart JKE et al., https://doi.org/10.1016/j.jad.2026.122265, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.