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

Summary

Ketamine and its enantiomer esketamine are effective in only 30-35% of patients with treatment-resistant depression. Increased serum brain-derived neurotrophic factor (BDNF) after a single intravenous dose has been proposed as a biomarker of antidepressant response, but effects under different treatment schedules are unclear. In a randomized, placebo-controlled trial of six-week, low-dose, oral esketamine (90 mg/day, three 30 mg intakes), depression severity and serum BDNF were measured in 54 patients at baseline, end of treatment, and after a four-week washout. BDNF levels did not significantly differ between esketamine and placebo groups during treatment or washout. An increase in BDNF occurred regardless of treatment condition.

Study at a glance

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.