When the U.S. Food and Drug Administration approved Spravato — a chemical cousin of ketamine — for treatment-resistant depression in March 2019, it brought immediate hope to the roughly 4 million people for whom traditional therapies have been ineffective. Esketamine, delivered via nasal spray in a doctor’s office, is the first new therapy to treat major depression in more than 30 years. But the treatment’s path to approval was a long one, highlighting the importance of federal support for medical research in academic medicine.
Dennis S. Charney, MD, has been one of the leading researchers behind the breakthrough treatment. The Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai, Charney began examining ketamine as an antidepressant while working as a psychiatry professor at Yale University in the late 1990s. It was a hard pill to swallow for fellow researchers, since ketamine had only been used as an anesthetic agent and a club drug until then.
Charney talked to AAMCNews about the early days of research, the medication’s limitations, and the powerful effects it will likely have on those suffering from treatment-resistant depression.
How does the esketamine nasal spray work?
Ketamine is characterized as an NMDA glutamate receptor antagonist. However, there is still much to be learned about how ketamine affects the brain, which results in its ability to rapidly improve the symptoms of depression.
Your research started more than 20 years ago. What inspired you to study the effects of ketamine on depression?
We were studying the biology of depression and working to develop better treatments. The available treatments block the reuptake of serotonin and/or norepinephrine and, while effective, take anywhere from weeks to months to work, and about a third of patients do not adequately respond. John Krystal, who is now chair of psychiatry at Yale School of Medicine, and I concluded another system must be involved in the causes of depression and how antidepressant drugs work. So, based upon our clinical research and preclinical studies done by others we thought that, perhaps, the glutamate system was involved.
In parallel, our research group was also studying ketamine and its effect on cognition and emotion. Those two lines of research came together and a small group of us decided, “Well, let us look at ketamine with patients who suffer from depression.” We gave low doses of ketamine and we saw a very rapid antidepressant effect — within a few hours.
Did you receive any pushback, given the drug’s other uses?
When our first ketamine paper was published in 2000 in the journal Biological Psychiatry, few believed the results. There were doubts about using ketamine because it was used recreationally. But we believed in our hypothesis. Subsequently, I went to the National Institute of Mental Health, and with Carlos Zarate and Husseini Manji, we replicated the initial findings of a rapid antidepressant effect of ketamine, this time in a group of patients with treatment-resistant depression. Those results were published in the Archives of General Psychiatry in 2006.
After you showed the antidepressant effects of ketamine, did patients start receiving the treatment?
Once we published the initial findings and others started replicating those studies, clinics were established to use ketamine off-label for depression. In the beginning, I was concerned about this because the drug was not approved. Ultimately, the pharmaceutical company Janssen conducted the necessary research studies with a form of ketamine, esketamine, to get FDA approval as a nasal spray.
Why does it have to be administered in the office? Is that a barrier to treatment?
Intranasal esketamine has some effects on blood pressure and may cause some behavioral effects in which the patient has a feeling of drowsiness and disassociation — a feeling of unreality. So, patients need to be observed for about 2 hours. You start out by getting it twice a week for a month, and then you can reduce the frequency to once a week. Millions of people who suffer from treatment-resistant depression will meet the criteria to get esketamine. These are patients who have suffered mightily and many have suicidal feelings. This will offer hope. The inconvenience of coming to the doctor’s office for patients suffering so badly, that is not going to be an issue.
What are the side effects? Is there potential for addiction?
When you first take ketamine, you can feel sedated and get a feeling of unreality, a feeling of disassociation from your environment. You can get somewhat of a high feeling. When you evaluate patients, you want to pay attention to the possibility of abuse. That is why the nasal spray will be given in the doctor’s office and not be taken home.
Have you been able to treat any of your patients yet?
We have done a lot of ketamine studies at Mount Sinai and we have had a lot of experience treating severely depressed patients. We are going to be developing a clinic to offer esketamine to patients who need it. The clinical work is done by our depression specialists, and we have gotten many requests from patients to receive esketamine.
What do you think the future holds for this treatment?
It is one of the most important discoveries in psychiatric treatment in decades and it offers hope for people to be relieved of terrible depression. Over the next number of years, it is possible other antidepressants with similar clinical effects and a better side effect profile will be discovered.
How do you make a transformative discovery?
The way it worked for us was a small group came up with an idea and then decided to be bold, to think outside of the box. I think that is how most major discoveries in medicine happen. It is a team sport. It is what every researcher hopes for — that they can ultimately make discoveries that will change the lives of their patients.