Foundation-Funded Research Refines Understanding of How New Rapid-Acting Antidepressant Works

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Lisa M. Monteggia, Ph.D. - Brain & behavior research expert on depression
Lisa M. Monteggia, Ph.D.

A key goal of current depression research is to develop faster-acting, more effective antidepressant medications than those currently available, which usually take effect only after many weeks of treatment and sometimes do not effectively alleviate symptoms at all.  

In a new study to compare how two candidate antidepressant medications—ketamine and memantine—work in the brain, 2010 NARSAD Independent Investigator Grantee Lisa M. Monteggia, Ph.D., who also received the Foundation’s Freedman Prize for Exceptional Basic Research by a Young Investigator in 2005, collaborated with 2012 NARSAD Distinguished Investigator Grantee Ege T. Kavalali, Ph.D., and Erinn S. Gideons, Ph.D., at the University of Texas Southwestern Medical Center at Dallas. Their findings were published online on May 27th in the Proceedings of the National Academy of Sciences, and built upon earlier work the group conducted to identify the mechanism of action for ketamine (published in Nature in 2011).

Ketamine has been shown to have a rapid antidepressant effect in patients with treatment-resistant depression. It can, however, produce adverse side effects, so the researchers wanted to explore why the similar, alternate medication memantine has not been shown to produce similar rapid-acting effects in clinical trials.

Using electrophysiological technology to observe the effects of each of the medications on brain cells in animal models, the researchers were able to identify key functional differences in how the seemingly similar compounds of ketamine and memantine function. Although both medications affect what are called NMDA (N-methyl-D-aspartate) receptors that facilitate communication within the brain, the signaling sparked by the NMDA receptors is different for each medication: the signaling sparked by the action of ketamine triggers an antidepressant response whereas the signaling sparked by memantine does not.

The researchers report that this new work provides “a novel framework on the necessary functional requirements of NMDAR-mediated neurotransmission” to produce rapid antidepressant responses.

Read the abstract.

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