In March, the U.S. Food and Drug Administration (FDA) announced the approval of the first wholly new medication to ease severe depression since fluoxetine (Prozac) debuted in 1988. The new treatment, a fast-acting nasal spray containing the active ingredient esketamine, will be marketed under the name Spravato.
The announcement may offer some hope for a select group of people who have major depressive disorder, especially those who have suicidal thoughts, and who aren’t helped by currently available oral antidepressants. Unlike oral depression medication, which can take weeks or even months to start working, esketamine has been shown to start helping within a matter of hours.
But esketamine isn’t for everyone with major depression and is not a first-line therapy. It’s for people with treatment-resistant depression who have had no success with at least two oral antidepressants. It isn’t used as a standalone treatment; esketamine is designed to be combined with an oral antidepressant such as fluoxetine, escitalopram (Lexapro), and sertraline (Zoloft). The FDA has placed tight restrictions on who can take esketamine and how it should be administered because of the drug’s serious side effects.
How was esketamine developed?
The origins of this “novel” therapy actually date back decades to the drug ketamine, which was approved by the FDA in 1970 for use as an anesthetic. Ketamine can cause hallucinations and out-of-body sensations, so it’s not surprising that illicit versions of it soon began to appear on the street as the party drug Special K. At the same time, doctors began to gather anecdotal evidence from patients with major depression that ketamine seemed to make them feel better-in some cases, dramatically better.
As controlled studies began to suggest that ketamine offered real benefit to some patients, a growing number of psychiatrists began prescribing it for depression “off-label,” that is, using a drug for a purpose other than the one it had been approved for. Over time, ketamine clinics began to spring up across the country, offering intravenous (IV) ketamine to treat severe depression.
Ketamine is a mixture of two mirror-image forms of the ketamine molecule, which differ in their effects on the body. Esketamine is the molecule responsible for ketamine’s antidepressant effects.
How does esketamine work?
Doctors aren’t exactly sure how esketamine improves symptoms of depression, but it seems to work via a different brain pathway than other antidepressants. And because it can take effect within only a few hours, it may be a potential lifesaver for people at acute risk of suicide.
How effective is it?
The FDA based its approval of esketamine, in part, on three short four-week clinical trials and one longer-term study, which yielded mixed results. In the short-term studies, patients (mostly white women in their 40s and 50s) were randomly selected to receive either esketamine or a placebo nasal spray. Both groups also took an oral antidepressant. In one short-term study, 53 percent of patients in the esketamine group reported significant improvement in one month compared with 39 percent in the placebo group. The other two short-term trials didn’t show significant improvement.
The longer-term trial, which followed patients for a year, looked at the duration of improvement in depression scores. That’s an important concern since many patients experience relapses. This study found that those taking a once-a-week maintenance dose of esketamine in addition to an oral antidepressant responded to treatment for a longer time than those on an oral pill alone. Larger double-blinded, placebo-controlled trials (in which neither patient nor doctor knows whether the patient is being treated with an active or inactive drug) are needed to gauge esketamine’s safety and effectiveness over a longer follow-up period.
Whether patients ages 65 and older will benefit remains an open question. So far, clinical trials haven’t rendered encouraging results. The study that found a statistically significant reduction in symptoms included only people under 65. A separate study that looked at patients 65 and above didn’t find any significant benefit.
The FDA approved esketamine at an accelerated pace through its “Fast Track” and “Breakthrough Therapy” designations. The FDA defines Fast Track as “a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need” and Breakthrough Therapy as a “process to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.” These designations have left many doctors wondering whether the mixed findings from the clinical trials-all funded by the drug’s manufacturer-were sufficient to determine the drug’s effectiveness and justify its approval.
How is it administered?
In theory, at least, a nasal spray should be a lot easier to take than a drug like ketamine, which is administered intravenously. But there’s a catch. Because esketamine can have serious side effects- including hallucinations and dissociation (feeling disconnected from yourself, your thoughts, your feelings, and time and space)-and has the potential to be abused, the FDA requires that esketamine be administered only in a doctor’s office or approved clinic.
Patients prescribed esketamine must also be taking an oral antidepressant. And while patients administer the spray themselves, they must be monitored for adverse effects by a health professional for two hours after getting a dose. Plus, they’re prohibited from driving from the time they take the medication until the next day following a restful sleep. The FDA’s restrictions on how esketamine must be given make treatment time-consuming and inconvenient for many people.
The recommended starting dose is two treatments a week for four weeks, then patients can cut back to one maintenance treatment a week. Esketamine can also be used temporarily to ease symptoms before oral antidepressant therapy takes effect.
How much does it cost?
According to Johnson & Johnson, which makes the new nasal spray, the wholesale cost of each treatment per dose will range from about $600 to $900 before discounts or rebates. That means twice-weekly treatments during the first month will cost around $5,000 to $7,000. Subsequent maintenance doses will be administered every one or two weeks. Even at one dose every two weeks, that’s a minimum of more than $1,000 a month for the indefinite future.
Now that the medication has received FDA approval, private insurers and Medicare are likely to cover some or all of the cost. In contrast, the off-label use of IV ketamine typically wasn’t covered, so patients had to pay out of pocket. Even so, IV ketamine treatments typically cost a fraction of the cost of Spravato. Some doctors have suggested that for patients who are uninsured or underinsured it may make sense to continue using the IV form of ketamine, because of its lower cost.
What are the drug’s risks?
As with any new medication, it’s important for your doctor to review your medical history and talk over the risks and benefits before starting treatment. Esketamine may increase the risk of heart attack or stroke in patients with unstable or poorly controlled high blood pressure and for those with certain forms of blood vessel disease. While patients taking esketamine are at risk for suicidal thoughts and behavior, the risk appears to be extremely small in adults. The most common side effects reported by patients who took esketamine in the trials included dissociation, dizziness, nausea, sedation, vertigo, decreased feeling or sensitivity, anxiety, lethargy, increased blood pressure, vomiting, and a feeling of being drunk.
Esketamine is not a magic bullet; in fact, it may only help a select few. The treatment regimen is complicated and time-consuming. But in rare cases of major depressive disorder with suicidal thoughts when psychotherapy and medicines with a longer and more proven track record haven’t been effective, it might be of benefit.