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Objectives: Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD)., Methods: Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards., Results: There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms., Conclusion: There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion., Competing Interests: Acioly L. T. Lacerda reports grants and personal fees from Janssen Pharmaceutical; personal fees from DaiichiSankyo, Cristália, Libbs, Pfizer, Myralis-Farma, Aché Laboratórios, Hypera-Pharma, and Sanofi-Aventis; grants from Eli-Lilly, Lundbeck, Servier-Laboratories, Hoffman-La-Roche, and Forum-Pharmaceuticals. Lucas C. Quarantini reports consulting fees from Allergan, Abbot, Janssen-Pharmaceutical and Lundbeck, and research fees from Janssen-Pharmaceutical. No other conflicts of interest declared concerning the publication of this article.