IMHRO Rising Star Award winner Dr. Lisa Monteggia's lab has developed a deeper understanding of how ketamine's fast antidepressant action works, suggesting a target pathway for future fast-acting drugs.
Antidepressant medications typically require a few weeks to start producing their therapeutic effects in patients. The drug ketamine has recently been discovered to produce antidepressant effects much more quickly-within hours of the first dose. The advantages of this speedier response are obvious, especially for patients in suicidal crisis. Figuring out the molecular basis for this rapid action will open the door to the development of improved antidepressants. Lisa Monteggia, Ph.D., Professor of Neuroscience at University of Texas Southwestern at Dallas, and winner of a 2011 Rising Star Award, started with the hypothesis that ketamine works by improving synaptic strength in specific regions of the hippocampus. Her team is using her grant to pinpoint on which end of the synapse, and through which mediating proteins, this enhancement takes place. Their ultimate aim, to reveal potential targets for future therapies, has already started to succeed.
Since Dr. Monteggia began working with her Rising Star grant, her team has discovered that the protein called BDNF, a growth factor for neurons in the brain’s memory-formation center, the hippocampus, is critical to ketamine’s antidepressant effect. While “normal” wild-type mice showed strong antidepressant-like behavioral responses after being given ketamine, mice which had BDNF removed from the hippocampus showed no such improvement. This evidence suggests that BDNF plays a governing role in ketamine’s fast action.
In 2012-13, Monteggia’s team has deepened their understanding of how BDNF mediates ketamine’s effect: They demonstrated that ketamine boosts neuroplasticity by triggering a BDNF-dependent increase in the incorporation of a specific type of receptors, which enables stronger signal transmission in hippocampal cells. In the synapses of mice with BDNF removed, ketamine dosing did not trigger this receptor incorporation. Apparently BDNF-mediated enhancement of neuroplasticity is integral to the antidepressant effect of ketamine. Monteggia says, “These findings also further link this specific signaling pathway to rapid antidepressant action and provide viable targets for therapeutic interventions against depression.”
Continuing research on that note in 2013-14, Monteggia’s team sought to understand why memantine, a drug which works similarly to ketamine, but without the characteristic side effect of inducing psychosis, fails to quickly reduce depression in patients. In experiments with mice, Monteggia has revealed that although memantine blocks the same receptor as ketamine, it does not trigger the biochemical reaction which augments BDNF expression-and thus fails to strengthen synapses and reduce depression. This discovery underlines the importance of this BDNF-promoting reaction as a target for future rapid antidepressants.
Over three years of Rising Star Award funded research, Dr. Lisa Monteggia has very finely honed our understanding of why ketamine improves so rapidly improves mood, and we hope drug developers will run with her results to create a new generation of fast-onset antidepressant medications.
We at IMHRO are very proud of Dr. Monteggia’s work and thank our donors to for enabling us to fund it.
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