Studying Ketamine’s Rapid Effects to Unlock Secrets for Developing Better Antidepressants
Lisa M. Monteggia, Ph.D.
Professor of Pharmacology, Vanderbilt University
Barlow Family Director, Vanderbilt Brain Institute
Scientific Council Member
2014 BBRF Distinguished Investigator Grant
2010 BBRF Independent Investigator Grant
2005 BBRF Freedman Prize for Exceptional Basic Research
2003, 2001 BBRF Young Investigator Grant
When you hear the word depression, everybody has an idea of what it means. A sad painting can make you feel unhappy or depressed. You can hear a sad song, or maybe you have had unhappy emotions—people talk about “feeling depressed.” Depression is a serious mental illness and it’s characterized by symptoms including anxiety, loss of pleasure, loss of appetite, sleep disturbances, and feelings of worthlessness, among others. There are a range of symptoms, which reflects the complexity of the disorder.
If you have 100 depressed people in a room, each could have somewhat different symptoms, even though they are all depressed. For a scientist to examine depression and try to really understand what causes it, that’s one of the major challenges with researching the illness.
Depression is now the leading cause of disability in the world, according to the World Health Organization. People are surprised by that—they think first of cancer or heart disease. Depression is a disease that can impact not only you, but your family, for decades. Thankfully there are medications to help treat the illness. Conventional antidepressants such as the SSRI and SNRI medicines (Prozac, Lexapro, Effexor, Paxil, etc.) have changed the course of this disease in many ways. These antidepressants work for many patients, typically taking a couple of weeks to several months to have an effect. Unfortunately, a large number of patients, 30% or more, are not helped by antidepressant medicines.
But the fact is: those individuals who don’t respond to antidepressants are often the ones most at risk for suicide. And if you look at the statistics on suicide, they’re staggering. The latest estimates put the number of suicides in the U.S. at over 44,000 per year, which is beyond tragic. Compare that number with the number of homicides over the past year, around 16,000. You have more than two and a half times the number of suicides to homicides, yet you rarely hear people talk about suicide.
Ten years ago the number of suicides in the U.S. was around 30,000. So we’ve seen a huge jump. The number of annual homicides over the last decade, in contrast, has remained quite stable. There’s been a lot of discussion of as to why there is this disparity. The reasons are being debated. But whatever the reasons are, the growing number of suicides highlights the need for better and faster-acting treatments for depression, including treatment-resistant depression.
HOW DO ANTIDEPRESSANTS WORK?
Beginning with the first grant that I received from BBRF, my team and I have focused on asking “How do antidepressants work?” We’ve all seen the commercials for these medicines on TV. They draw a neuron and they show it releasing serotonin—the neurotransmitter—and then they say, “There’s less serotonin in depression and if you take an antidepressant, now you have more serotonin and you feel better.” But the reality of it is, there’s very little data showing that less serotonin is what causes depression. Moreover, while typical antidepressants may increase serotonin, they do that very quickly, yet antidepressants take weeks before you feel better. So while the serotonin surge is important, you don’t have this immediate antidepressant effect. This leads us to conclude that other things have to happen.
My lab was able to identify an important component of neuronal signaling, and a particular growth factor called BDNF (brain-derived neurotrophic factor) that appears to be required for an antidepressant response. A variant of the gene that directs cells to make BDNF contains a DNA “spelling” error that can change the activity of both the gene and the BDNF protein it encodes. Some studies have suggested that individuals who have this genetic variant may have an attenuated response to antidepressants.
As we were studying this question, research was published indicating that the anesthetic drug ketamine, when given at a sub-anesthetic dose, can have rapid antidepressant effects. Ketamine has been around for a long time. At moderate doses it can be a drug of abuse; it has many street names including “Special K.”
What has been recently discovered is that at a very low dose, one that isn’t going to induce anesthesia or trigger psychosis, ketamine can be effective in refractory depression patients, some of whom are among those most at risk for suicide. Refractory depression refers to situations in which patients are not helped by one or more standard courses of approved antidepressant therapies.
With ketamine, the drug is infused intravenously in a clinical setting over 40 minutes. Patients can stabilize very quickly and they actually experience an antidepressant effect, sometimes as rapidly as within 30 minutes. If a patient doesn’t start to experience a beneficial effect within 2 hours, then ketamine is probably not going to be effective for them.
What’s remarkable is that a single infusion can have effects on some patients for several days to a week, and sometimes longer. It’s not because the drug is staying around in your body—it isn’t. So it’s doing something in your brain to produce these lasting effects.
We became very interested in studying this drug. We want to use it as sort of a Rosetta Stone, if you will, for two important reasons. First, it may help us understand the mechanism behind how antidepressants work—a mechanism we’ve never seen previously. Second, ketamine is well characterized to have effects on a particular protein in the brain called the NMDA receptor. It’s a receptor on certain neurons and ketamine appears to block its activity.
Could we show that by blocking this receptor, ketamine is triggering an antidepressant effect? And if we could do that, could we think of ways of manipulating this pathway to reduce potential side-effects that can occur with ketamine? (Ketamine can have side-effects, such as dissociation—a very uncomfortable “out-of-body” feeling. It is also potentially addictive.)
On the question of “How does ketamine work?” our data shows that it really does block the NMDA receptor, and that it has very specific effects on a particular signaling pathway. If we experimentally interfere in that signaling pathway, ketamine doesn’t produce an antidepressant effect, at least in experiments we’ve conducted in animals.
A NOVEL FORM OF PLASTICITY
Perhaps more surprising, we were able to show that ketamine, by blocking the NMDA receptor and affecting signaling, triggers a novel form of plasticity in the brain. Plasticity is the ability of neurons to alter the strength of their connections. Ketamine appears to affect plasticity in a new and unexpected way. We’ve tested drugs similar to ketamine that have been tried clinically, like memantine, which also blocks the NMDA receptor, and found that memantine does it slightly differently. And we can show that memantine does not have the same effect on signaling and that it doesn’t trigger this novel plasticity. We only see this plasticity with the rapid antidepressant action. What we think may be happening is that this type of plasticity may be a common mechanism in how antidepressants work— but whether this plasticity is actually “fixing” depression, we’re not yet able to say.
While ketamine is probably having many different effects on the brain, not all of them are responsible for its antidepressant effects. We think that ketamine is having effects on a region of the brain called the hippocampus. Our idea is that antidepressants in general, not only ketamine but typical antidepressants also, are initiating plasticity processes in the hippocampus that then impact the prefrontal cortex and other brain regions. So in studying how ketamine triggers a rapid antidepressant effect, we hope to backtrack and use that knowledge to understand how conventional antidepressants work.
We’ve been able to show, then, that blocking NMDA receptors induces a novel form of plasticity. We think it’s a form of what we call “homeostatic” plasticity. A different form of plasticity than the type involved in learning, for example. What we think may be happening is that this type of plasticity may be a common mechanism in how antidepressants work. But whether this plasticity is actually fixing depression, we’re not sure. We’ll see—but these are the focus of ongoing experiments right now. If we can understand, “What is this plasticity doing in your brain? Why is it important?” then we can think about administering other drugs that trigger this kind of plasticity and perhaps find other ways to generate antidepressant effects.
One reason this is important is that even among individuals who are given ketamine, about 20% to 30% don’t respond. Why not? Well, if you can identify other ways to trigger antidepressant effects, we might be able to develop a treatment option for these non-responders. Similarly, it may be, that the 30% to 50% of individuals who don’t respond to conventional antidepressants may have a variation or a deficit in a gene somewhere along the pathway in which conventional antidepressants need to exert their therapeutic action. Maybe this is why such people don’t respond to ‘ We can now ask what the same mutation in 10 different people leads to, and how much the effects vary between the cells we generate from each person’ Changes in plasticity—the strength of connections between neurons—are likely crucial in depression and in treatments that relieve it. conventional SSRI antidepressants. It’s not necessarily one mutation; it could affect proteins anywhere along the pathway.
In other words: our goal is to see if we can find other ways to trigger an antidepressant effect, and then, try to parse out who can respond to different types of antidepressants. That would be the ultimate goal. But right now what we’re trying to do is understand how ketamine triggers a rapid antidepressant effect, as well as trying to understand how it’s sustained. If, as we have shown, ketamine triggers a novel form of plasticity, what is this plasticity doing to the brain? Why are we only seeing it with a drug that produces a rapid antidepressant effect?
Also, we have seen clinically that if you give a second dose of ketamine, individuals seem to have a cumulative effect—that if you give the second dose, the novel plasticity that we see is even further enhanced. We’re trying to understand why. How is this really working and can we target this to maintain an antidepressant effect?
THE IMPORTANCE OF BASIC RESEARCH
We’re starting to understand why people respond and why they don’t to conventional antidepressants and to rapid-acting ones like ketamine. It’s all about trying to develop better treatments, faster treatments, treatments that can be maintained—things we all regard as extremely important, in view of the immense toll that depression takes on our society.
This is the power of basic research. We’re seeing it play out right now in this time of COVID. Development of the vaccines was phenomenal, but it wasn’t a matter of people just going into a lab and emerging a few weeks later with vaccines that work. That research, like ours, has been built on decades of basic research. Great advances don’t come from out of nowhere. And in our work on the brain, there’s a level of complexity that is unique; we have much yet to discover. People worry about having a heart attack. The reality is, if you have a heart attack, you get to a hospital and there’s a lot they can do for you in terms of treatments and saving your life. A great deal is known about the heart. But with the brain, so little is known, still.
We’re getting to piece things together and with the help of new technologies things are moving quickly. Our advances over the past decade have been remarkable. I think the future looks really bright. We’re continuing to build on what we have learned. This is going to be important for depression. And lately, as we’ve seen in our work on bipolar disorder, it’s interesting: with some of the drugs that help patients, such as lithium, we’re seeing them elicit a novel form of plasticity, as well. It’s slightly different than what we see with an antidepressant effect, but again, there are plasticity mechanisms that are engaged, which we’re trying to understand. Perhaps this approach could also have implications for understanding schizophrenia; we don’t yet know.
My take-home point is about the importance of basic research for discovery —discovery that may not come today, but which is the basis for advances in treatments. Even though we may not be where we want to be right now with disorders of brain and behavior, our progress provides a real source of hope.
Written By Peter Tarr, Ph.D.
Click here to read the Brain & Behavior Magazine's May 2021 issue
