Esketamine is the first new antidepressant to be approved in decades—but it comes with some caveats.

By Amanda Gardner
Updated: April 12, 2019

The new antidepressant approved yesterday by the FDA achieves a number of firsts. It is the first new antidepressant to be approved in decades that works in an entirely novel way, the first antidepressant to come in nasal spray form, and the first to work in a very short time rather than in weeks or even months. And for people suffering from major depressive disorder for whom nothing else has worked, it may offer a new chance at recovery.

The news comes with much hope and excitement—but also several caveats. "People are saying this is a game changer because it seems like it works well for refractory depression, meaning people who have failed to respond to conventional antidepressant medications and behavioral treatments," Soonjo Hwang, MD, a psychiatrist with the University of Nebraska Medical Center, tells Health. "Also, it seems to work in 24 to 48 hours, so there's a very rapid resolution of symptoms."

Timothy B. Sullivan, MD, chair of psychiatry and behavioral science at Northwell Health at Staten Island University Hospital, echoes these thoughts: "There is a significant number of people who suffer from major depression who either respond partially or not well at all to the current available treatments. Anything that promises to help address the needs for that population is really exciting."

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The new drug is approved for patients with treatment-resistant depression. That means patients who have not responded to "at least two antidepressant treatments given at adequate doses for an adequate duration in the current episode," according to the FDA. Like any new medication, it comes with many questions; clinical studies before FDA approval are limited in the number and type of patient they include, meaning that more information only comes to light when new drugs reach the "real world."

In the case of esketamine (sold as Spravato), one of these concerns is that it's related to ketamine, which has been used as an anesthesia and to get high in the form of the once-popular party drug Special K. There's a concern that this new antidepressant may carry a risk of addiction and substance abuse.

Esketamine seems to help alleviate depression by acting on the NMDA/glutamate receptor, which is different from more recently popular antidepressants. But esketamine also seems to have an effect on the opiate system. This is not a direct effect, but a "downstream" effect, says Dr. Sullivan, yet there's an obvious potential impact on public health.

"My concern is that we don't really how it gets people un-depressed," Mark George, MD, a psychiatrist and neurologist at the Medical University of South Carolina in Charleston, tells Health. "There are complex interactions with different neurotransmitter systems. If this works through the NMDA and glutamate mechanism, that's really great, but if it's working through the opiate system, we need to be prepared."

Ketamine could work in part by restoring microcircuits in the prefrontal cortex of the brain, according to new research published in the journal Science. New technology allowed the researchers to access the brains of living mice. Their findings suggest that ketamine speeds up the process of healing that occurs after a depressive state.

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Data so far indicates that esketamine is safe to use, "but it has to be used in a very well-regulated way to prevent issues related to addiction/substance use," Dr. Hwang says.

That includes getting the drug in a certified doctor's office or clinic. According to the FDA, the nasal spray is administered by the patient him or herself while supervised by a medical professional. The nasal spray never leaves the office and must be taken with an oral antidepressant. The patient can leave the health care facility only after the care provider says it's OK (usually about two hours).

The official FDA approval also warns of possible side effects such as feeling sedated and problems with attention, judgment, and thinking (called "dissociation"). Patients are required to sign a form attesting that they understand they need to make arrangements to safely get home and that they cannot drive or use heavy machinery on the day they receive the drug.

Some 16 million people in the U.S. have major depression, and one-third of them have not responded well to available treatments and may therefore be considered to have treatment-resistant depression.

"We need better treatments for sure," says Dr. Hwang. "I don't think this is going to be a miracle cure for depression. There are a lot of areas we need to address." But the FDA approval, he adds, is a step toward having another viable and safe treatment for major depression.

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This post was originally published on March 6, 2019 and has been updated.

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