Unlocking the Mysteries of the Glutamate System
Ketamine, Similar Compounds Emerging as Mood Disorder Treatments
Sanjay J. Mathew, MD, vice chair for research at Baylor College of Medicine and staff physician at the Michael E. Debakey VA Medical Center in Houston, Texas, has long been interested in the brain’s glutamate system and how it could be manipulated with substances such as ketamine to treat conditions including depression and suicidal ideation.
At this year’s Psych Congress, Dr. Mathew, who is also director of Baylor’s mood and anxiety disorders program, will share the top 5 things that mental health clinicians should know about therapy with ketamine and the esketamine nasal spray newly approved by the US Food and Drug Administration (FDA). Below, he discusses his research into ketamine, how it works in the body, ongoing research into the compound, and similar agents that are in development.
Q: How did you first become involved with research into glutamatergic agents such as ketamine?
A: I've been involved ever since my faculty position at Mount Sinai [School of Medicine], where we were interested in the glutamate system broadly for its potential impact in neuroplasticity and we were studying agents such as riluzole, which is approved in amyotrophic lateral sclerosis (ALS), and repurposing it for depression and generalized anxiety disorder. And then in 2006, we noted the work by [Carlos A.] Zarate, and prior to that John Krystal and Dennis Charney at Yale [School of Medicine] had done initial studies with IV ketamine. Dennis Charney, who was my mentor at Mount Sinai, influenced us to try to replicate and extend some of the work of Zarate. And so we've been involved since that early time testing ketamine as an antidepressant but also looking at it in suicide and looking at it from a mechanistic point of view, trying to understand how it may be working in patients.
Q: What did you find exciting? Why did you think it was something you wanted to spend time working on?
A: It was really a paradigm shift, in that it was a way to rapidly potentially get a patient better, get them out of a depression. Many of these patients had been depressed for several decades and they report that they'd been on multiple trials and even if the trials of selective serotonin reuptake inhibitors (SSRIs) or other medications worked, they would lose effectiveness, and they would relapse. So it was an almost sort of endless cycle of partial hope and then despair. Some of these patients had had electroconvulsive therapy (ECT). Some of them had had multiple hospitalizations and suicide attempts and so they were really seeking alternatives. They were exploring neurostimulation. Around that time, transcranial magnetic stimulation (TMS) had become FDA-approved. And there was clinical trials in deep brain stimulation. Ketamine offered this hope that you could get out of the despair or hole of depression and get better quickly and so that was what was exciting, I think, for patients. And then for me, as a clinician, to actually see that awakening, if you will, of patients for several hours after the infusion, that would persist in some patients for several days—and we've had patients even with several week responses—was very gratifying to see. The challenge of course is how did you maintain that wellness as inevitably the ketamine effect wears off and patients would relapse. And so that's where we've been devoting a lot of our efforts to identify the best ways to maintain the benefit.
Q: In your research, what have you found most striking about ketamine and similar agents?
A: Well, it seems that across different clinical programs, different research programs in the US and internationally, ketamine no matter what the formulation—be it IV, intranasal, subcutaneous, and so on— does appear to have this rapid onset of benefit within 50% plus of patients, even with resistant depression, and it also appears to have antisuicidal properties that may be independent of depression. And that's been a replicable finding. Now with the FDA approval of intranasal esketamine, we've seen data even in very large numbers supporting that notion, that you can get a patient better, quicker, and get them out of the suicidal state. So that research over the last 10 to 15 years has now matured to the point where we actually now have an FDA-approved variant of ketamine that will now be available to potentially many more thousands of patients.