Here’s Why Experts Say Esketamine, The Newest Antidepressant In Decades, Isn’t A Cure-all

For people struggling with depression, standard antidepressants like SSRIs or SNRIs don't always offer relief. In fact, research shows that one-third of depression patients have experienced no improvements while taking oral antidepressants, a problem known as "treatment-resistant depression." Last week, the FDA approved esketamine, a new medication specifically aimed at those with treatment-resistant depression, marking the first time a new antidepressant has been approved in the U.S. in 30 years.

The drug, a chemical cousin to the anesthetic ketamine, targets a different set of brain chemicals than traditional SSRIs, according to The Washington Post. Esketamine doesn't just have the potential to help patients who haven't benefited from traditional antidepressants; it may also improve symptoms much faster than other medications. In fact, clinical trials have shown that some patients using esketamine experienced an initial reduction of depressive symptoms in two hours, a far cry from SSRI medications that can take weeks to start working.

However, while esketamine — which will be available under the brand name Spravato in coming weeks — definitely offers new options for people struggling to treat their depression, there's a lot we still don't know about it, from how long-term use might impact our health, to how effective a treatment it will prove to be in the world at large.

How Does Esketamine Work?

Oral antidepressants, like SSRIs and SNRIs, work by regulating the amount of several neurotransmitters found in the brain: serotonin, norepinephrine, and dopamine. These medications increase the amount of these neurotransmitters found in the brain, on the theory that people who have depression have low levels of them.

Esketamine, however, works through a different mechanism. Rather than increasing certain neurotransmitters in the brain, it inhibits the action of NMDA receptors, which according to Spravato manufacturer Janssen "is thought to help restore connections between brain cells in people with treatment-resistant depression."

"[Esketamine] does work in a different way on a different receptor that has never been targeted before," Dr. M. Lindsey Hedgepeth Kennedy, a clinical pharmacy specialist at the UNC Medical Center and residency program director for the PGY2 Psychiatric Pharmacy Residency, tells Bustle. "If a person has not had any response with multiple antidepressants, certainly a trial of esketamine may be warranted." But, Kennedy says, while there has been lots of research showing that it works, there's not yet any clear evidence regarding exactly why or how esketamine specifically helps depression sufferers who haven't responded to SSRIs.

She also suggests that people considering esketamine, or any other medication, utilize talk therapy in addition to their drug regimen, in order to fully understand and manage their depression.

Where Did Esketamine Come From?

Esketamine didn't come out of nowhere; it's almost exactly the same drug as the generic medical anesthetic ketamine, which was invented in the 1960s. Many of us have heard of ketamine only in the context of its illegal use as a "party drug" nicknamed Special K, but a number of psychological studies in recent decades have suggested the drug's potential as an antidepressant.

In response to this research, hundreds of clinics offering intravenous ketamine treatment have popped up in the U.S. in recent years. These clinics provide ketamine to patients "off-label," since it is not approved by the FDA as an antidepressant, and as a result, it is offered for a wider variety of ailments in these clinics.

For Dr. Steven L. Mandel, M.D. an anesthesiologist, master of clinical psychology, and president of Ketamine Clinics of Los Angeles, this means that in addition to patients with treatment-resistant depressions, he's also treated patients with bipolar II, postpartum depression, and PTSD with ketamine infusions at his clinic.

Mandel tells Bustle that, contrary to some press framing ketamine as a magic bullet that can be used on its own to recover fully from mental illnesses, ketamine is best used as part of larger therapeutic treatment involving talk therapy, as Dr. Kennedy says. Ketamine treatment "is not something that is 'done to the patient," he says, "it is something done with the patient. Active participation in the treatment pays enormous dividends."

Another issue with this off-label use has to do with the clinics that administer it. Though some ketamine clinics are run by experienced individuals with advanced training, there is no national certification system for them and they are minimally regulated, which has led to widespread concern within the medical community. A 2018 investigation by Scientific American found that some ketamine clinics did not follow the American Psychiatric Association's guidelines for ketamine treatment, did not have a licensed mental health professional on staff, did not utilize a thorough patient screening process, and exaggerated claims about ketamine's antidepressant properties.

Mandel says that for anyone looking into treatment at a ketamine clinic, "It's crucial you vet your provider to ensure they are qualified and have an appropriate setup."

How Is Esketamine Different From Ketamine?

Though Mandel tells Bustle that esketamine is "not chemically different" from ketamine, the two drugs still present different benefits and drawbacks for patients considering them.

Ketamine is generally administered intravenously. Because it is not FDA approved as depression treatment, patients generally can't get insurance coverage for the treatments, which can cost anywhere from $500 to $1,000 per infusion, according to Scientific American. Since ketamine clinics are not working from a single model of treatment, different clinics offer different numbers of infusions per patient, on different schedules, over different periods of time. But the Journal of the American Medical Association found that a number of clinics administered two to three infusions a week, for a course of two to three weeks, with the option for future "booster shots" or additional courses of treatment as needed.

Esketamine, meanwhile, is administered through a nasal spray. Because it is FDA approved, patients with insurance may be able to get at least part of their treatment costs covered, which will run from $4,720 to $6,785 for the first month (not including costs related to facilities or physicians). Its price point, however, likely places it beyond the grasp of people without insurance.

The methods of administration also plays a role in the efficacy of the treatment. Mandel calls nasal spray "an inferior route of administration," and the Verge reports that 70 percent of those who tried ketamine IV infusions reported improved mood, while around 45 percent of subjects reported improved mood from nasal ketamine.

Side effects for both treatments include disassociation, dizziness, nausea, and increased blood pressure, which is why patients must remain at the clinic for at least two hours following administration, and must agree to not drive for the rest of the day

Mandel also says that, as currently approved, esketamine is available only in specific fixed doses, which does not allow medical professionals to adjust for individual patients.

Who Should Consider Using Esketamine?

All decisions about new medications or treatments should be made with a mental health professional. That said, there are some additional considerations to take into account if you're thinking about trying esketamine.

To begin with, esketamine is currently only approved to treat treatment-resistant depression. A person can be diagnosed with treatment-resistant depression after trying two other antidepressant medications for at least six weeks each with no improvement to mood. In these cases, esketamine could potentially provide an alternative to more invasive therapies for TRD, like electroconvulsive therapy and repetitive transcranial magnetic stimulation. Due to its fast-acting nature, esketamine might also be used by medical professionals in emergency situations — in cases where someone is dealing with self-harming or suicidal ideation, for example.

Kennedy cautions, however, that not every person who doesn't respond to oral antidepressants has treatment-resistant depression. Sometimes, doctors can misdiagnose bipolar disorder, personality disorders, or other mental illnesses that don't respond to antidepressants as depression.

There are also a few conditions that may prevent patients from benefiting from esketamine treatment. Mandel suggests that patients currently experiencing "active psychosis or mania" avoid ketamine-based treatment for the duration of their symptoms, as ketamine can temporarily heighten those symptoms.

Kennedy says that esketamine treatments can increase blood pressure, making not an ideal treatment for anyone with blood pressure issues. Additionally, she says that habitual users of psychedelic drugs should avoid the drug. She also urges caution for any patients with PTSD using esketamine; in those situations, "an extra level of safety should be present, whether it be monitoring for longer than two hours, or calling the next day or [a few days later] to ensure the patient is safe."

How Is Esketamine Administered?

Unlike daily SSRIs, which are typically consumed in pill form, esketamine will be self-administered as a nasal spray in a clinical facility. It's currently indicated for use twice a week, for a four week course of treatment, with the possibility of future "booster shot" treatments. After the nasal spray is administered, patients will stay at the clinic for two hours, so that medical professionals can watch for side effects.

Additionally, patients can't just rely on esketamine to treat their depression; they're also required to regularly take an oral antidepressant medication. (It isn't immediately clear why this requirement is in place, since esketamine is recommended for people who have not responded to oral antidepressants.)

What Are The Risks Of Esketamine Use?

Right now, researchers don't know much about the risks of long-term esketamine use. While some studies have indicated that long-term ketamine use can lead to liver damage and bladder inflammation, much of the information we do have is derived from studies of recreational ketamine users, who take much larger doses of the drug than would be provided in a medical setting.

"Like any new drug, we don’t know the long term effects," says Kennedy. "Esketamine was studied up to four months, but depression can be a life long illness." Additionally, she says, since the drug has only been tested on a small group of patients, we don't yet know all the adverse reactions that might occur when a broader group of people are taking it. "We just don’t know the true benefit or risk until more people use it," says Kennedy.

We also don't yet know how effective esketamine will be. Though much coverage of ketamine seems to hail it as a miracle cure for depression, the New York Times reports that many veteran physicians believe claims about the drug's effectiveness are exaggerated. Like SSRIs before it, we won't know how well esketamine actually works for a wide range of patients until a wide range of patients try it.

"In a sense, some of the hype is warranted, but esketamine is not a panacea," Kennedy says. "Depressive symptoms don’t magically disappear with a few doses." For some people living with depression, esketamine might be a real help — but it won't fix everything. At the end of the day, it's not a magic bullet; it's just another medication.

If you or someone you know is seeking help for mental health concerns, visit the National Alliance on Mental Health (NAMI) website, or call 1-800-950-NAMI(6264). For confidential treatment referrals, visit the Substance Abuse and Mental Health Services Administration (SAMHSA) website, or call the National Helpline at 1-800-662-HELP(4357). In an emergency, contact the National Suicide Prevention Lifeline at 1-800-273-TALK(8255) or call 911.