Psychiatry · Medical Literature
Serum brain-derived neurotrophic factor following oral esketamine in treatment-resistant depression: Results from a randomized placebo-controlled trial.
Abstract
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. 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. 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. 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.
Clinical relevance
Does six weeks of daily low-dose oral esketamine (90 mg/day in three divided doses) increase serum brain-derived neurotrophic factor (BDNF) levels compared to placebo in patients with treatment-resistant depression (TRD), and does any change in BDNF correlate with antidepressant response or drug metabolite levels? __SNAPSHOT__ {"studyDesign":"Secondary biomarker analysis of a multicentre, double-blind, randomized placebo-controlled trial (RCT)","setting":"Three Dutch academic and specialist psychiatric institutes: University Medical Centre Groningen (UMCG), Parnassia Psychiatric Institute (The Hague), and Pro Persona Depression Expertise Centre (Nijmegen); conducted February 2017–February 2021","sampleSize":"n=54 (blood samples available from a subset of the parent RCT; total parent RCT n=111); per-arm allocation not reported in available abstract","population":"Adults with treatment-resistant unipolar depression (TRD), moderate-to-severe severity (Hamilton Depression Rating Scale [HDRS] total score >18), having failed at least two adequate antidepressant trials; many were receiving concomitant antidepressant medications","intervention":"Oral esketamine 90 mg/day (three 30 mg intakes daily) for six weeks","comparator":"Matched oral placebo administered three times daily for six weeks","primaryOutcome":"Change in serum BDNF levels between esketamine and placebo groups; secondary: correlation of BDNF changes with depression severity (HDRS) and ketamine metabolite levels","followUp":"10 weeks total (6-week treatment phase + 4-week washout); assessments at baseline, end of treatment (week 6), and end of washout (week 10)","fundingSource":"Not reported in available abstract"}
Key findings
The primary biomarker finding was that change in serum BDNF levels during the six-week treatment phase did not differ significantly between the esketamine and placebo groups, and this null difference persisted through the washout period. Notably, a statistically significant within-group increase in BDNF was observed across both conditions over time (F(1,50) = 4.606, p = 0.037), indicating a non-specific rise in BDNF irrespective of treatment allocation. No correlation was found between BDNF changes and changes in depression severity (HDRS) in the esketamine arm, and BDNF changes did not correlate with esketamine metabolite levels. These results are internally consistent with the parent RCT's primary clinical outcome, which also showed no difference between esketamine and placebo on the HDRS (p = 0.626; reported in Smith-Apeldoorn et al., 2024). No NNT or NNH is calculable from the available biomarker data. No specific adverse event data were reported in the abstract for this sub-study; safety data are available in the parent RCT.
Practice implications
This study establishes that six weeks of daily low-dose oral esketamine at 90 mg/day does not elevate serum BDNF levels above placebo in patients with TRD, and that the non-specific within-sample BDNF increase observed over time is likely attributable to concomitant antidepressant medications or other confounders unrelated to esketamine. The findings do not support serum BDNF as a valid biomarker of antidepressant response in this dosing context, challenging extrapolation from acute intravenous ketamine studies—which used a single high-exposure dose with rapid CNS NMDA receptor saturation—to repeated, low-dose oral regimens that achieve substantially lower systemic and CNS drug concentrations due to extensive first-pass metabolism (oral bioavailability 8–24%). It remains unresolved whether this null BDNF result reflects a fundamental decoupling of the BDNF pathway from antidepressant effect in oral esketamine, or whether the 90 mg/day dose was insufficient to reach the pharmacological threshold required to engage synaptic plasticity mechanisms. Findings apply specifically to adults with unipolar TRD receiving a fixed low-dose oral regimen; they cannot be extrapolated to individually titrated higher oral doses, intravenous infusion, intranasal esketamine, or patients without prior antidepressant treatment. Limitations of abstract-only availability preclude full assessment of effect size magnitudes, confidence intervals, or subgroup analyses. No practice change is warranted from this analysis alone; it primarily informs biomarker research design and underscores the importance of dose-response considerations in ketamine pharmacobiology. __LIMITATIONS__ 1. Secondary biomarker sub-study design: BDNF analysis was not the pre-specified primary outcome of the parent RCT, raising the possibility of a hypothesis-generating rather than confirmatory framework. 2. Small sample size (n=54 of 111 enrolled), limiting statistical power to detect modest between-group BDNF differences and reducing generalizability. 3. Only abstract available for full methodological review; confidence intervals, effect sizes for BDNF changes, and detailed demographic data are not reportable here. 4. The parent RCT demonstrated no clinical efficacy at this dose, making it difficult to disentangle whether the null BDNF result reflects the dose being too low to engage either clinical or biological pathways, versus BDNF being genuinely uninformative as a biomarker. 5. Concomitant antidepressant medications in many participants likely elevated peripheral BDNF non-specifically in both arms, obscuring any esketamine-specific signal. 6. Serum BDNF is a peripheral proxy for central neurotrophin activity and may not accurately reflect CNS BDNF changes relevant to synaptic plasticity. 7. The fixed low-dose regimen (90 mg/day orally) does not represent current real-world oral esketamine practice, which increasingly uses individually titrated higher doses; results may not apply to higher-dose protocols. 8. Restriction to three Dutch specialist centres may limit generalizability to other healthcare systems or less treatment-resistant populations. 9. Funding source not reported in the available abstract, precluding assessment of potential sponsorship bias. __BOTTOM_LINE_CATEGORY__ low_certainty __BOTTOM_LINE__ Six weeks of daily low-dose oral esketamine (90 mg/day) did not increase serum BDNF levels relative to placebo in TRD, consistent with the absence of clinical efficacy observed in the parent RCT at this dose. The non-specific BDNF rise seen in both arms likely reflects concomitant antidepressant use or other confounders, not an esketamine-mediated effect. Serum BDNF should not be used as a biomarker of oral esketamine response at this dose, and caution is warranted when extrapolating BDNF findings from single intravenous ketamine studies to other routes or dosing schedules.