The U.S. Food and Drug Administration has approved a drug called esketamine—the first major new depression treatment to hit the market in decades.
The drug, developed by Janssen Research & Development (a pharmaceutical company of Johnson & Johnson), is administered in the form of a nasal spray as opposed to an oral pill. Designed specifically for people suffering from the most extreme forms of treatment-resistant depression, esketamine could affect millions of people living in the U.S. who are at high risk of suicide due to existing therapies’ inability to manage their disease. The nasal spray will be administered only in approved and certified treatment centers, and will be restricted to people who have tried at least two other antidepressants without success. Patients who receive the drug will also need to be monitored for at least two hours every time they use it.
“This is the first truly novel mechanism that has been presented in over 50 years,” says Dr. Gerard Sanacora, a professor of psychiatry and director of the Yale Depression Research Program.
Unlike antidepressants like Prozac, which appeared on the scene in 1987, esketamine is a glutamatergic agent—that is, it targets glutamate, the most abundant neurotransmitter in our brain and central nervous system. “About 60-80 percent of all the cells in the brain use glutamate as their primary chemical messenger,” Sanacora says. Previous treatments have all targeted the monoamine system, which is comprised of a different set of neurotransmitters: dopamine, noradrenaline, and serotonin.
In the 1990s, researchers began accruing evidence that the glutamate system was disrupted in patients suffering from depression. They also knew that ketamine, known as “Special K” in illicit party drug-speak, targets the glutamate system—so scientists decided to investigate exactly how ketamine works in the brain and whether or not it could alleviate symptoms of depression.
In 2000, Dr. Dennis Charney, along with Dr. John Krystal, published the first study showing that intravenous infusions of ketamine produced rapid (within a few hours) antidepressant effects.
“I don’t think anybody was anticipating a rapid onset,” Sanacora says. That’s a big deal, since drugs like Prozac and Zoloft often take weeks or months to have any noticeable effect.
Charney and his colleagues at the National Institutes of Health then replicated the study in more treatment-resistant patients. At Icahn School of Medicine at Mount Sinai (ISMMS), where Charney is now dean as well as professor of psychiatry, neuroscience, and pharmacological sciences, he and others conducted the first study of the intra-nasal version of the drug, as well as the first study that showed the neurobiological response could be repeated. Since then, research groups around the world have begun to take heed of the drug’s potential.
Janssen's derivative product—called esketamine because it is a close cousin of ketamine—blocks a particular glutamate receptor, the NMDA receptor, from absorbing the glutamate it secretes. As a result, connections between neurons are restored and the brain’s neuroplasticity increases through the production of more synapses. (Disclosure: Charney is named as co-inventor on patents filed by ISMMS relating to the treatment of treatment-resistant depression. ISMMS has a licensing agreement with Janssen related to these patents, and it receives payments from Janssen under that agreement. Charney, by extension, is entitled to a portion of those payments.)
“When we undergo chronic stress, neurons actually shrink,” says Dr. Scott Russo, a professor of neuroscience and director of the Center for Affective Neuroscience at the Icahn School of Medicine at Mount Sinai. “It’s thought that they underperform. Ketamine rejuvenates those cells” particularly in the prefrontal cortex, a region of the brain responsible for higher cognitive functions like judgment and decision-making.
But Russo notes that the blocking of the glutamate receptor is not indisputably responsible for the antidepressant effects. While that mechanism is certainly a catalyst, a series of “downstream effects” occur after the receptor is blocked; a single wave or ripple within that cascade of events could actually be what’s giving patients relief. “I’d want to see [additional] animal studies to prove that [the blocking of NMDA receptors] is the sole mechanism of action,” he says. For example, one study showed that the brain's system of opioid receptors might be involved.
In addition, Russo says that there is evidence to suggest that ketamine can reduce inflammation—a burgeoning topic in neuropsychiatric research—but again, it’s likely not a primary functioning of the drug.
Despite these nuances, Russo is enthusiastic about the drug's approval. "I think it's a game changer," he says. "I haven’t seen that type of discovery in my lifetime—I was probably five years old when the last drug came on the market. I hope this starts a chain reaction of new drugs in psychiatric medicine."
Not everyone is waxing poetic about esketamine's promise. Dr. Erick Turner, a psychiatrist at Oregon Health and Science University, served on the FDA advisory committee that evaluated the drug—but he wasn’t present at the review panel earlier this month. He says that Johnson & Johnson fell short of the required number of adequate and well-controlled trials (two) that indicate a drug’s efficacy (see the second paragraph of page 9 in this FDA briefing document for an acknowledgement of the exception the FDA made to this rule).
“As a former regulator, I worry that this has been overly-hyped and that it’s not going to live up to expectation,” Turner says. He also has concerns about monitoring, distribution, and insurance coverage. Still, Turner concedes that the new mechanism is exciting. “I would like to see it explored further.”
Turner notes that a combinatory drug called Symbyax, released in 2009, appeared to have an effect of similar magnitude. “I guess I haven’t seen any evidence that this [esketamine] is better than what we already have,” he says, pointing to studies in elderly patients that show ketamine’s effect sometimes doesn’t take hold in as quickly as a few hours—that it could instead take up to weeks.
Nevertheless, that speed of onset is, according to proponents of esketamine, one of its fundamental advantages.
“As a clinician, it’s really hard to tell a patient, ‘I know you’re feeling terrible, but I’d like you to start taking this medicine. You may feel worse for a week or two or three before you start to feel better, but just keep taking it,’” Sanacora says. “When somebody’s suffering from depression, every day feels like an eternity—and now you’re telling them to wait weeks and possibly months before I can you tell if it’s even going to work. So this is a huge advance.”
In 2016, an estimated 16.2 million adults in the United States had at least one major depressive episode. Of those, 37 percent did not receive treatment. A drug like esketamine—which is at low risk for abuse (though the drug's label will list possible side effects and warn that there is a risk for misuse) and has only moderate side effects—could be an option for those people who might really need it.
“This shouldn’t be something everybody jumps to,” he says. “But there are clearly situations where you need a rapid onset.”
“The approval opens up a whole new vista of potential treatments,” Sanacora says. He praises his colleagues—Charney, Krystal, and others—for experimenting with ketamine so many years ago.
“Serendipity favors the prepared mind,” he says. “They were playing in the right sandbox.”