Research News

Research Snapshot: Professor discovers signaling pathway that lets ketamine act as a rapid antidepressant

By Aran Sullivan 


Ketamine has been gaining interest over the past several years as a fast-acting antidepressant. Past research shows that ketamine has antidepressant effects, especially for those who have treatment-resistant depression. Lisa Monteggia, professor of pharmacology and director of the Vanderbilt Brain Institute, furthered her prolific research on the topic by investigating a specific mechanism of action for ketamine’s antidepressant action within the brain.  

photo of Lisa Monteggia
Lisa Monteggia (John Russell/Vanderbilt University)

The key molecule, brain-derived neurotrophic factor (BDNF), or its receptor was selectively deleted from two places in the hippocampus, a seahorse-shaped brain structure that plays a major role in memory. Monteggia’s results found that BDNF and its receptor are required in the hippocampus for ketamine to produce antidepressant effects. 


This study showed that ketamine requires expression of BDNF and its receptor in specific regions of the hippocampus to act as an antidepressant. “The identification of a synaptic locus for ketamine’s antidepressant actions will hopefully contribute to the further development of rapid acting antidepressants,” Monteggia said.  

The study also found that ketamine strengthens connections between synapses in the hippocampus, which is thought to contribute to the rapid nature of its antidepressant effects.  


The identification of a specific synaptic connection within the hippocampus that enables ketamine’s rapid antidepressant action provides novel insight into how antidepressant effects may be initiated in the brain.  Monteggia hopes these findings can contribute to the mapping of a neural circuit essential for antidepressant action, which would be useful for the development of more rapid and effective antidepressants.  

This research indicates that further investigation of BDNF’s necessity in other brain regions is warranted, and that researchers should should test other rapidly acting antidepressants on the circuitry found in this study.  


Support for this research was provided by the National Institute of Mental Health grants MH070727, MH081060 and MH066198.  


The study, “A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action,” was published online in the journal Cell Reports on August 17.