One of the pioneer investigators of ketamine for depression explains what its recent approval for a severe form of the condition means for patients running out of options.
Dennis Charney, MD
This week, the US Food and Drug Administration (FDA) approved esketamine nasal spray (Spravato) for as a new drug for treatment-resistant depression. Though the Janssen Pharmaceuticals novel drug—the first novel mechanism-of-action therapy approved for depression in 30 years—has been the subject of recent discussion for its potent efficacy and potentially adverse effects, it’s a conversation Dennis Charney, MD, has been hearing for years.
Charney, the Dean of Icahn School of Medicine at Mount Sinai, was among the pioneering team of Yale University investigators to assess ketamine in patients with depression. In an interview with MD Magazine®, he shared his perspective on the drug’s progression to the market, the approval’s significance for patients with treatment-resistant depression, and what’s to come next in potential ketamine care.
MD Mag: What is your history of research in ketamine for depression?
Charney: When I was at Yale, my colleagues—particularly John Krystal, MD—and I had been studying the mechanism of action of anti-depressant drugs and the biology of depression. Back then, the focus was the role of serotonin and norepinephrine. The available anti-depressant drugs were serotonin and norepinephrine reuptake inhibitors. Given that those drugs took weeks and months to work, and didn’t work in a pretty health percentage of patients with depression, we were also working at what other neurochemical systems could be involved.
Ultimately, we thought that maybe glutamate, a major neurotransmitter in the brain, could be involved. In pursuing the role of glutamate in the late 1990s, we decided to look at the effect of ketamine, which is an NMDA and glutamate receptor antagonist, in patients with depression. We administered a low dose of ketamine to patients with major depression. In the first study, when we administered to 7 patients, to our surprise we observed that the depressive symptoms were reduced within a few hours. It was rapidly active. And we published that in 2000.
And it didn’t get much attention. It was like crickets. It just kind of sat there. I don’t think people believed you could treat depression that fast, and it was such a different mechanism, that it wasn’t pursued. So I left Yale for the National Institute for Mental Health, where I ran the research programs focusing on depression, anxiety, and post-traumatic stress disorder (PTSD). I told our group, “Let’s try ketamine again, this time studying a group with more severe depression.” The patients would have had to have failed at least 2 treatments with the traditional anti-depressants. And we found in a sample size of about 18 that ketamine had rapidly reduced depressive symptoms. We published our second paper in 2006.
Once that got published, it drew a lot of attention. Research groups across the country, and even around the world, began to study ketamine in depression and—for the most part—began replicating those findings. Ultimately, we patented the use of ketamine and its derivatives for treatment-resistant depression. We licensed the patent to Janssen, who then pursued large-scale studies with esketamine to get approval from the FDA.
What issues did the medical community draw with such research?
Ketamine, in significantly higher doses, was a recreational drug called “Special-K,” so there was some concern about that. There still is some concern about that, that it could be used as a drug of abuse. Early concerns focused between those 2 facts—including that the first study only included 7 patients.
What are the symptoms and therapy history of a patient with treatment-resistant depression, which would lead them to being a candidate for ketamine?
Depression is among the most concerning medical diseases. It’s common. The estimates vary, but I would say it’s about 20-25 million Americans who at some point have suffered from major depression. It affects your life, in terms of employment, relationships, your ability to experience pleasure. And in those patients who don’t respond to the traditional anti-depressant, those symptoms are magnified—in that the patient feels hopeless, that they’re never going to get better. In the worst cases, they are suicidal.
The fact that esketamine has been shown to effectively treat treatment-resistant depression, in many patients, this offers hope. Previously, there was not much hope.
Jeffrey Lieberman, MD, mentioned concerns to MD Mag about whether dosing strategies for ketamine have been properly set by clinical trials. Do you imagine that’s something that will be addressed early into real-world assessment?
What traditionally happens when a drug is approved is—based on a couple thousand patients or less—once it gets to the market, you want to carefully observe for side effects. In the case of esketamine, it’s going to be carefully administered. That patient is going to have to come to the office to get a dose and be observed for a couple of hours. They’ll get it twice per week.
I agree with Jeff Lieberman that we want to follow the response of patients on esketamine once it reaches the market.
For what other indications could ketamine be assessed?
Here at Mount Sinai, we published the first study of ketamine in PTSD. And that was a positive study that needs to be replicated. We’re in the process of doing a second study to see if we get the same results. And other groups are looking at PTSD.
We were also the first to observe it was associated with anti-suicidal ideation effects, and I know JAMA (The Journal of the American Medical Association) and a few other groups are pursuing that now. That would be a very important indication.
Investigative microdosing therapies for psychiatric conditions seem to be getting more consideration from research groups and manufacturers. Do you think US healthcare will continue to trend in this direction?
I would say that we have to use scientific approaches to study treatments. That means the studies have to be controlled, designed to be safe, and that efficacy is carefully assessed. No matter what treatment is being assessed, you have to follow those scientific approaches. For conditions that don’t have effective treatments available, there should be an open mind. But careful studies of safety and efficacy are always going to be required.
In light of the sudden resignation of FDA Commissioner Scott Gottlieb, MD, could you speak to the FDA’s role in aiding the progression of novel therapies such as ketamine to the market?
The FDA is absolutely critical. It’s our safe-guard. We need it to be a rigid scientific organization, because the American people depend on the assessment of efficacy and safety for all the treatments that address the needs of humankind. We need the FDA to be a very strong, effective organization.
And I should mention that Dr. Gottlieb is a graduate of Mount Sinai. We’re proud of what he’s done.