Lisa Monteggia, professor of pharmacology, and collaborators have provided evidence about how ketamine works as a rapid-acting antidepressant in the brain. The research reinforces the hypothesis that the glutamate N-methyl-D-aspartate (NMDA) receptor on synapses, at the point where neurons communicate, is the drug’s target.
The current understanding is that once ketamine is administered, it blocks those NMDA receptors. This changes a neural biochemical pathway, which elicits more protein production and thus rapid effects in the brain—including a novel form of plasticity that acts as a cellular correlate to rapid antidepressant’s effect.
“What we’ve shown is that the pathway ties directly to NMDA receptor function,” said Monteggia, also Barlow Family Director of the Vanderbilt Brain Institute. “This bolsters the overall notion that the NMDA receptor is ketamine’s target.”
The team looked into how reelin—a protein that controls cells’ interactions in the brain—is involved in ketamine’s antidepressant effects. Joachim Herz, a professor of molecular genetics, neurology and neuroscience at UT Southwestern and a world-leading expert in reelin, contributed his knowledge to the research. They found that mutations or impairments to reelin could result in patients’ not experiencing ketamine’s antidepressant effects.
“By looking at the drug’s target through a different lens, we provide further evidence that regulating the NMDA receptor function is important to ketamine’s positive effects,” Monteggia said.
WHY IT MATTERS
Ketamine can provide rapid antidepressant action—relief in as little as two hours that can be sustained for days to weeks—for individuals resistant to typical antidepressants and thus most at risk of suicide. These typical anti-depressants work in only 50 percent to 60 percent of patients and take four to five weeks to demonstrate whether they are working at all. By strengthening the research community’s fundamental understanding of how ketamine works in the brain, Monteggia and her collaborators are solving a riddle that may ultimately help people find relief from a dire situation in the form of new antidepressant drugs.
Further, the idea of trying to understand why ketamine works in some patients but not others is important for everyone. “Depression is a heterogenous disorder; it is rather remarkable that antidepressants and ketamine work in as many patients as they do,” Monteggia said. “By understanding the target and how mutations or impairments affect the drug’s mechanism, we can develop fast-acting antidepressants that target other populations.”
While ketamine has a short half-life, its antidepressant qualities persist for days or weeks at a time. Monteggia intends to further investigate ketamine’s long-term effects to understand how these may influence drug discovery and design.
This work was supported by NIH grants MH070727 and MH081060 (LMM) and MH066198 (ETK), the National Research Foundation of Korea Basic Science Research Program funded by the Ministry of Education grant 2016R1A6A3A03008533 (JWK), National Heart, Lung, and Blood Institute grant R37 HL063762, the National Institute on Aging grant RF AG053391, the National Institute of Neurological Disorders and Stroke and NIA grant R01 NS093382, BrightFocus grant A2016396S, the Bluefield Project to Cure frontotemporal dementia and a Harrington Scholar Innovator Award (JH).
The article “A key requirement for synaptic Reelin signaling in ketamine-mediated behavioral and synaptic action” was published in the journal Proceedings of the National Academy of Sciences on May 18.
Ege Kavalali, professor of pharmacology and William Stokes Chair in Experimental Therapeutics, contributed to the research, as well as postdoctoral researcher Ji Woon Kim.