A drug most well-known for creating an illicit euphoria amongst club-kids and ravers is finding a second life as a legitimate treatment for depression. Here we detail what it is, how it works, and the hope it may bring to millions.

In March, the US Food and Drug Administration (FDA) approved a drug called Spravato, an adult anti-depression drug that is administered in the form of a nasal spray. 

Also known as  Esketamine Nasal Spray , the anti-depression treatment represents a considerable step forward in how medical professionals approach medicating those with depression symptoms.

As the first drug of its kind, the goal is to provide patients that suffer from depression a drug that could succeed where other medications have failed.

According to Tiffany Farchione, MD, who is the acting director of the FDA’s Center for Drug Evaluation and Research Division of Psychiatry Products:

“There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition.”

The prospect of a new treatment for those that struggle with depression and are unresponsive to current therapies could not come at a better time.

Anxiety, depression, and their related disorders impact 40 million US adults annually – more than 15% of the adult population. Yet, only 37% of those individuals that suffer from depression receive any treatment.

Compounding the issue is that almost a third of adults that have depression or depression-like symptoms are resistant to most forms of treatment. A sobering stat that gives reason to celebrate any new breakthroughs.

But what exactly is esketamine, and how can a nasal spray help someone who suffers from depression?

Let’s look closer at what esketamine is, including what it does and some of its side effects, and how it may succeed where other drugs had failed.

What Is Esketamine?

Esketamine, as the name implies, is derived from the Schedule III drug, ketamine. If that name sounds familiar, it’s because ketamine gained notoriety as a popular club drug. It’s history, however, goes back more than 50 years.

Developed in the late 1950s, ketamine was first used as a fast-acting anesthetic for those in surgery. Towards the end of the 1960s, its use grew to include military applications during the Vietnam War. It quickly became the most popular anesthetic during the latter years of the war. 

Low dosages were beneficial at reducing pain and when used alongside certain sedatives, made them even more useful. Perhaps its greatest attribute during this time was proving a safer alternative to morphine.

Ketamine also gained widespread use in veterinary medicine as a means for inducing anesthesia (alongside a reversible sedative), and in a more limited capacity, as a painkiller for animals. It’s popularity though as a dissociative psychedelic amongst youthful club goers is where ketamine use garnered the most attention. 

In recent years, however, ketamine found a new purpose, with discoveries showing it to generate positive outcomes in people who suffered from debilitating and treatment-resistant bouts of depression.

While their chemical makeup is nearly identical and both can be used to treat depression, esketamine is a far stronger version of ketamine. 

What Is Esketamine Nasal Spray and How Does it Work?

The version of esketamine approved by the FDA sells under the name Spravato, a nasal spray developed at Johnson & Johnson (in partnership with Janssen Pharmaceuticals). The spray’s approval is contingent upon it being used in concert with an oral antidepressant. 

For an individual to qualify for the prescription spray, they must have used at least two other antidepressant treatments – unsuccessfully – prior to the use of Spravato.

To understand how esketamine works, it helps to know how antidepressants, in general, affect the brain.

Antidepressants treat a number of conditions – everything from clinical depression to obsessive-compulsive disorder (OCD) to post-traumatic stress disorder (PTSD) –  by regulating the chemicals in the brain. They are shown to increase levels of serotonin and noradrenaline, both neurotransmitters that are most directly associated with a person’s emotional state. 

Eskatamine exhibits similar properties – regenerating brain cells and their neurological connections – but demonstrates the additional benefit of working much faster. In some cases, a patient on esketamine will start feeling the effects from within a few hours to a couple of days.

 

The vast majority of other antidepressants don’t start working until several days to several weeks (even months in some instances) after a patient begins a specific regimen.

The importance of a faster-acting antidepressant is a critical step forward in depression treatment. The ramp-up time for a typical medication still leaves a window for someone suffering from depression to fall into a deeper decline. There also stands the possibility for them to harm themselves or someone else as they wait for their medication to take effect.

Eskatamine carries with it the potential to significantly close that window, and the trails resulted in plenty of optimism.

Spravato approval came from Phase III results of two studies, where the esketamine spray (along with an oral antidepressant) showed “statistically significant, clinically meaningful rapid reduction of depressive symptoms as compared to placebo.”

Another trail resulted in almost 70% of subjects responding positively within four weeks of receiving esketamine versus a placebo group, where only 52% had a positive response to their regimen. 

In addition, this study also succeeded in showing esketamine patients with a 51% reduced relapse rate against those taking the placebo centered treatment. 

Side Effects of Esketamine Nasal Spray

In spite of its promise and FDA approval,  Esketamine Nasal Spray , as with almost all medications, is not without its risks.

The most common side effects include those regularly associated with taking medication – dizziness, nausea, headaches, and sleepiness. 

However, as a drug that interacts with and regulates chemicals within your brain, there are a number of more severe effects that a patient may encounter. These include fainting, spinning sensation, anxiety, a sense of drunkenness, or dissociation from yourself or your thoughts and feelings of being disconnected from space and time.

Esketamine may also make depression symptoms worse, leading to abnormal behavioral changes, a deeper state of depression, or thoughts of suicide. While a patient is wise to be aware of these potential side consequences, they do mirror the risks of most other antidepressants in this regard.

One of the more unique aspects of esketamine – and potentially its biggest disadvantage – is its addictiveness and the potential for abuse by patients. 

Of course, most every prescription medication possess this prospect of addiction, but few have the reputation and popularity as a cheap, widely used, and highly addictive party drug (which carried with the street name “Special K”). Some professionals worry about its potential to mirror the opioid epidemic.

Dr. Mark George, Medical University of South Carolina professor of psychiatry, radiology, and neurosciences, points out:

“My concern about this compound is that it is a disguised form of opiates. I’m alarmed that there is pretty clear evidence [that] the way ketamine works is through the opioid system.” He also goes on to add, “If this is the mechanism that ketamine acts through to treat depression, its effects won’t last, and people might develop a tolerance to the drug, possibly even becoming addicted.”

In its release, the FDA acknowledges these concerns. Tiffany Farchione, MD, noted:

“Because of safety concerns, the drug will only be available through a restricted distribution system, and it must be administered in a certified medical office where the health care provider can monitor the patient.”

In spite of the hazards, any step forward in better treating depression is considered a win by many in the medical profession.

David Olson, assistant professor of chemistry, biochemistry and molecular medicine with the University of California, Davis echoes this:

“I think that the FDA approval of ketamine is a huge landmark in the history of treating neuropsychiatric diseases. Ketamine really represents a leap forward in terms of new ideas for attacking depression and related neuropsychiatric diseases.”

As we noted earlier, the administration of the esketamine nasal spray requires an oral antidepressant to be taken at the same time. 

The reason for this, versus taking esketamine by itself, is that in the studies that led to its approval, all subjects were on an oral antidepressant. Due to the seriousness of depression, researchers did not want to leave their subjects without any medication during the trials. 

Conclusion

From a long, divergent history that is equal parts good and bad,  Esketamine Nasal Spray stands to make a huge impact in an area long misunderstood, and difficult to treat. Breakthroughs such as this reflect just how far the medical field has come in treating depression and other mental conditions.

Although uncertainty still surrounds  Esketamine Nasal Spray (to be fair, this can also be said of any number of other FDA-approved medications), it’s difficult to ignore patient testimonials that claim:

“I’m now able to appreciate a wider range of emotions than when I was depressed. My long-term goals have taken shape and actually seem attainable.”