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Original Research

Brain-Derived Neurotrophic Factor and Initial Antidepressant Response to an N-Methyl-d-Aspartate Antagonist

Rodrigo Machado-Vieira, MD, PhD; Peixiong Yuan, MD, PhD; Nancy Brutsche, MSN; Nancy DiazGranados, MD; David Luckenbaugh, MA; Husseini K. Manji, MD, FRCPC; and Carlos A. Zarate Jr, MD

Published: September 8, 2009

Article Abstract

Objective: A model has been proposed to explain the pathophysiology of mood disorders based on decreased neurotrophin levels during mood episodes; treatment with antidepressants and mood stabilizers is associated with clinical improvement. This study investigated whether changes in brain-derived neurotrophic factor (BDNF) levels are associated with the initial antidepressant effects of ketamine, a high-affinity N-methyl-d-aspartate (NMDA) antagonist.

Method: Twenty-three subjects aged 18 to 65 years with DSM-IV major depressive disorder (treatment resistant) participated in this study, which was conducted between October 2006 and May 2008. The subjects were given an open-label intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and rated using various depression scales at baseline and at 40, 80, 120, and 230 minutes postinfusion. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale score. BDNF levels were obtained at the same time points as depression rating scale scores.

Results: Despite a significant (P‘ ‰<‘ ‰.001) improvement in MADRS scores after subjects received ketamine treatment, no changes in BDNF levels were observed in subjects after they received ketamine compared to baseline. Also, no association was found between antidepressant response and BDNF levels.

Conclusions: This study demonstrates that ketamine’s rapid initial antidepressant effects are not mediated by BDNF. Further studies are necessary to shed light on the neurobiological basis of these effects.

Trial Registration: Identifiers: NCT00024635 and NCT00088699

Submitted: August 29, 2008; accepted November 5, 2008.

Online ahead of print: September 8, 2009.

Corresponding author: Carlos A. Zarate Jr, MD, 10 Center Dr, CRC, Unit 7 Southeast, Room 7-3445, Bethesda, MD 20892 (

Volume: 70

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