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Is Esketamine the Game-Changer for Depression We Want?

Esketamine works in a way different than other anti-depressants — but it’s not clear if it could be a long-term solution for patients

Spravato, the brand name for esketamine, a newly approved option for treatment-resistant depression.

Spravato, the brand name for esketamine, has been approved by the FDA for use on treatment-resistant depression.

Janssen Pharmaceutica

Last week, the FDA announced that it had officially approved Spravato, a brand-name nasal spray containing esketamine, a chemical cousin of ketamine, to treat depression. The drug was hailed by many as a game-changer, as it’s proven to be an effective therapy for people with treatment-resistance depression (TRD), or approximately 30-percent of all people with depression. But how effective is it at actually curing the illness, and approximately when could it become a viable long-term solution for the estimated 16.2 million adults with depression? Here’s what you need to know.

What is esketamine, and how does it work in treating depression?
As has been widely reported, esketamine is a chemical cousin of ketamine, the drug that’s most well-known as an anesthetic in high doses, as well as the club drug Special K.

“Esketamine is essentially ketamine,” says Dr. Dan Iosifescu, associate professor of psychiatry at NYU Langone Health who specializes in treating people with treatment-resistant depression. “Ketamine is a combination of esketamine and r-ketamine…for all practical purposes, there may be slight differences, but it’s the same molecule, just differently wrapped up. 99.9% of everything you say about ketamine is what you would say about esketamine.” (And much like ketamine, some people who have taken esketamine report mind-altering side effects, although Iosifescu says only one out of six subjects in his studies of esketamine did so.)

As a treatment for depression, the drug is distinct from other, more common antidepressants, such as Prozac and Zoloft, because it operates via a different mechanism in the brain. While other antidepressants modulate a group of chemicals in the brain called monoamines, esketamine targets glutamate, which is found to be in abundance in the brains of people with depression.

The fact that it works in an entirely new way, Iosifescu says, means that it could be successful for the approximately 30 percent of people with depression who do not respond to traditional antidepressants (TRD is defined as people who have taken at least two antidepressants for at least six to eight weeks and at an appropriate dose, with no effect.)

Because esketamine has been found to take effect much more rapidly than traditional antidepressants — “no less than an hour” after a dose has been administered, says Iosifescu — the drug particularly has promise for people who are experiencing an acute episode of major depressive disorder and may even be having thoughts of self-harm. In fact, numerous studies have pointed to its potential benefits as a drug to be administered to someone admitted to an emergency room with suicidal ideation.

“You’re talking about someone who’s waited for a few months, finally decided to start something, took another additional months to find no benefit, or someone who felt miserable for 9-plus months, and you can imagine their impact on life, their family, etc.,” says Iosifescu. “So having a method by which you can stop this process and then even if it’s not a cure but just something helps dramatically and improves things is very valuable.

Are there any drawbacks to taking esketamine for depression?
Essentially, there’s one big one: we don’t know whether it’s appropriate to recommend long-term use. We know that esketamine works in treating depression, and we know that it works rapidly — but we don’t quite know whether it’s a viable long-term solution, as there are documented negative health effects to taking large amounts of the drug over a lengthy period of time.

“I think the most important is: well, are people supposed to take ketamine forever if that works for them and nothing else did? And we know right now there is potential for some brain damage with too much ketamine,” Iosifescu says.

To be fair, that data comes from two sources, neither of which may be totally applicable to its use as a treatment for depression: studies of the brains of people who abuse ketamine (who typically take much higher doses and don’t take pure ketamine), and studies of the brains of mice and rodents who have been dosed with ketamine for a long period of time. But such studies have somewhat daunting implications for ketamine’s long-term use, with side effects including bladder toxicity, cognitive problems, and, in the mice’s case, lesions on the brain.

“The point is that there may be a level at which too much ketamine is too much. And we don’t know that level,” Iosifescu says. And given that the FDA has only recommended administering ketamine twice a week for four weeks under doctor’s supervision , “it’s not clear beyond that” whether it could cause health problems. Additionally, the procedure is expensive (the cost of the month-long treatment ranges from between $4,720 to $6,785) and time-consuming, as patients must receive Spravato only under the supervision of a doctor. That’s why Iosifescu is hopeful that researchers will ultimately develop oral tablets that can be taken at home and would not have the downsides of esketamine itself, but would perhaps operate according to a similar mechanism in the brain.

At the end of the day, most mental health experts seem to believe that the research in support of esketamine benefiting people with treatment-resistant depression (particularly short-term and acute incidences of depression) is cause enough to celebrate — albeit with a slight caveat.

“I hope and expect that the field would be able to find an oral treatment that would not have the downsides of ketamine and would be able to used in the long term,” Iosifescu says. It’s clear that ketamine works for people with depression: “Now the question is, what do you do after it works?”

 

Anyone experiencing a crisis is encouraged to call the National Suicide Prevention Hotline at 1-800-273-8255 or contact the Crisis Text Line by texting TALK to 741-741.

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