Role of BDNF in the pathophysiology and treatment of depression: Activity-dependent effects distinguish rapid-acting antidepressants

Eur J Neurosci. 2021 Jan;53(1):126-139. doi: 10.1111/ejn.14630. Epub 2019 Dec 20.


The pathophysiology and treatment of depression have been the focus of intense research and while there is much that remains unknown, modern neurobiological approaches are making progress. This work demonstrates that stress and depression are associated with atrophy of neurons and reduced synaptic connectivity in brain regions such as the hippocampus and prefrontal cortex that contribute to depressive behaviors, and conversely that antidepressant treatment can reverse these deficits. The role of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), has been of particular interest as these factors play a key role in activity-dependent regulation of synaptic plasticity. Here, we review the literature demonstrating that exposure to stress and depression decreases BDNF expression in the hippocampus and PFC and conversely that antidepressant treatment can up-regulate BDNF in the adult brain and reverse the effects of stress. We then focus on rapid-acting antidepressants, particularly the NMDA receptor antagonist ketamine, which produces rapid synaptic and antidepressant behavioral actions that are dependent on activity-dependent release of BDNF. This rapid release of BDNF differs from typical monoaminergic agents that require chronic administration to produce a slow induction of BDNF expression, consistent with the time lag for the therapeutic action of these agents. We review evidence that other classes of rapid-acting agents also require BDNF release, demonstrating that this is a common, convergent downstream mechanism. Finally, we discuss evidence that the actions of ketamine are also dependent on another growth factor, vascular endothelial growth factor (VEGF) and its complex interplay with BDNF.

Keywords: ketamine; neurotrophic factor; stress; synaptic plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Brain-Derived Neurotrophic Factor*
  • Depression / drug therapy
  • Ketamine* / pharmacology
  • Ketamine* / therapeutic use
  • Vascular Endothelial Growth Factor A


  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Vascular Endothelial Growth Factor A
  • Ketamine