Repeated Low-Dose Oral Esketamine Did Not Increase BDNF in Treatment-Resistant Depression
Key Clinical Summary
- A randomized, placebo-controlled study published in the Journal of Affective Disorders found that 6 weeks of low-dose oral esketamine (90 mg/day) did not increase serum brain-derived neurotrophic factor (BDNF) levels compared with placebo in 54 patients with treatment-resistant depression (TRD).
- Serum BDNF increased modestly over time across both treatment groups, but the change was not associated with oral esketamine treatment, improvement in depression severity, or ketamine metabolite levels.
- The findings suggest that repeated low-dose oral esketamine may not achieve the pharmacological threshold required to engage BDNF-related synaptic plasticity, although the authors note this remains uncertain.
Patients with TRD receiving repeated, low-dose oral esketamine did not experience greater increases in serum BDNF than those receiving placebo, according to findings published in the Journal of Affective Disorders. The study also found no relationship between changes in BDNF and improvements in depressive symptoms or ketamine metabolite levels.
Study Findings
Ketamine and esketamine have demonstrated antidepressant efficacy in approximately 30% to 35% of patients with TRD, and previous studies of single intravenous ketamine administration have suggested that increased serum BDNF may serve as a biomarker of antidepressant response. However, whether BDNF expression changes with repeated oral dosing has remained unclear.
To address this question, investigators analyzed biomaterials from a randomized, placebo-controlled clinical trial evaluating 6 weeks of oral esketamine in adults with TRD. Participants received 90 mg/day of oral esketamine administered as three 30-mg doses (n = 27) or placebo (n = 27). The parent trial found no significant difference between treatment groups on the primary outcome, the Hamilton Depression Rating Scale (HDRS).
The current analysis included 54 patients with serum samples collected at baseline, the end of treatment, and after a 4-week washout period. Depression severity and serum BDNF concentrations were measured at each time point. Repeated-measures analyses of variance assessed treatment effects, while Pearson correlation analyses assessed associations between changes in BDNF, depression severity, and ketamine metabolites.
The researchers found no significant differences in BDNF changes between the oral esketamine and placebo groups during either the treatment phase or the washout period. Although serum BDNF increased over time across the overall study population (F1,50 = 4.606; P = .037), this increase occurred regardless of treatment assignment.
Within the esketamine group, changes in serum BDNF were not correlated with changes in depression severity or ketamine metabolite concentrations.
Clinical Implications
The findings suggest that repeated, low-dose oral esketamine does not produce measurable increases in serum BDNF beyond those observed with placebo in patients with TRD. While BDNF has been proposed as a marker of synaptic plasticity and antidepressant response, these results do not support its use as a biomarker of response for this dosing strategy.
The lack of a treatment-specific effect is also consistent with the parent clinical trial, which found no significant improvement in depressive symptoms with oral esketamine compared with placebo. However, the authors emphasize that the results warrant further investigation.
Expert Commentary
“While consistent with the limited clinical efficacy of this treatment regimen, it remains uncertain whether this reflects an unreached pharmacological threshold for synaptic plasticity,” wrote first author Sara Massetti, PhD candidate, senior author Jens H. van Dalfsen, PhD, Department of Psychiatry, University Medical Centre Groningen, Groningen, the Netherlands, and coauthors.
“Antidepressant co-medication and general BDNF confounders might have increased peripheral BDNF levels irrespective of treatment condition, a finding to consider when designing future studies,” they concluded.
Reference
Massetti S, Smith-Apeldoorn SY, Veraart JKE, et al. Serum brain-derived neurotrophic factor following oral esketamine in treatment-resistant depression: Results from a randomized placebo-controlled trial. J Affect Disord. Published online July 16, 2026. doi: 10.1016/j.jad.2026.122265.
