Jonathan D. Raskin, Ph.D.

Making Meaning


The New FDA-Approved Antidepressant: Your Questions Answered

Esketamine is the first antidepressant to target glutamate, but concerns remain.

Posted Mar 11, 2019

Last week the FDA (U.S. Food and Drug Administration) approved esketamine as a totally new kind of antidepressant. Below are questions that psychotherapists (as well as clients) may be asking about it and the answers they need to know.

Q. What is esketamine?

A. Esketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Put more simply, esketamine blocks receptors for glutamate, an excitatory neurotransmitter in the brain. This decreases glutamate transmission. Esketamine is closely related the more well-known anesthetic drug, ketamine.

Q. Why does blocking glutamate receptors relieve depression?

A. Glutamate is an excitatory neurotransmitter. By blocking glutamate transmission, esketamine has not only anaesthetic and dissociative effects, but has also been observed to alleviate depressed mood.

Q. Why is esketamine a big deal compared to other antidepressants already on the market?

A. Esketamine is the first antidepressant to target glutamate. All other FDA approved antidepressants affect monoamine neurotransmitters—mostly serotonin, but also norepinephrine and dopamine. It is worth mentioning that, to a lesser extent, esketamine also prevents the reuptake of dopamine, which makes more available. So, even though its main impact is on glutamate, it has some effect on dopamine too.

Q. Will esketamine be an over the counter pill, like other antidepressants?

A. No. The only form of esketamine the FDA has approved for use so far will be sold as a nasal spray.

Q. So I’ll be able to get a prescription for it, go to the pharmacy, and pick up esketamine nasal spray to use at home?

A. Definitely not. Patients prescribed esketamine will only be allowed to use it under strict medical supervision in a doctor’s office or clinic.

Q. Why are there such severe restrictions?

A. Because esketamine can be habit-forming. Its mirror drug, ketamine, is sold illegally as the addictive street drug “Special K.” Thus, the restrictions are intended to prevent people from becoming addicted to esketamine. Due to its anesthetic effects, patients will also have to sign paperwork indicating that they won’t drive or operate heavy machinery on the days they are administered esketamine. They will be required to stay at their doctor’s office for two hours after taking esketamine or until judged alert enough to leave.

Q. That sounds a little scary. Why use esketamine instead of less habit-forming oral antidepressants that affect monoamine neurotransmitters?

A. Because those oral antidepressants don’t always work. Esketamine is only intended for use in patients who haven’t responded to at least two oral antidepressants—in other words, it is reserved for patients whose depression is deemed “treatment resistant.” 

Q. So when oral antidepressants don’t work, the doctor might switch you to esketamine instead?

A. Not exactly. When patients are prescribed esketamine, they will be given it in addition to (as opposed to in place of) an oral antidepressant.

Q. Oral antidepressants such as the SSRIs (selective serotonin reuptake inhibitors) take a few weeks to have an effect. Is that true for esketamine too?

A. No. One of the reasons esketamine and ketamine have been studied as alternative drug treatments for depression is that they are fast acting, taking effect between a few hours and a few days. Of course, the downside of that is that their effects wear off more quickly, as well.

Q. How often is esketamine administered?

Twice per week for the first 4 weeks, once per week for the next 4 weeks, and then once every other week after that (although in some cases, dosing may remain at once per week if deemed necessary).

Q. We’ve mostly been talking about esketamine. But what about ketamine, which I hear is also used to treat depression?

A. The FDA has only approved esketamine at this time. However, you are correct that some clinics have been using ketamine to treat depression. However, when they do so they are doing it off label. The FDA hasn’t approved ketamine as a treatment for depression because more extensive research investigating its effectiveness remains to be done.

Q. If doctors can use ketamine to treat depression without it being approved by the FDA, does FDA approval really matter?

A. Yes, it still matters. Even though some doctors use it without FDA approval, until such approval is granted ketamine treatments are unlikely to be covered by health insurance and cannot be advertised as approved treatments for depression. With its new FDA approval, esketamine becomes more readily coverable under insurance and can be legally marketed as a depression remedy.

Q. Oh, so now that is has FDA approval, am I likely to begin seeing ads for esketamine as a treatment for depression?

A. Probably, though I'm not privy to the advertising strategies being used to sell esketamine. However, when you do eventually see advertisements, you'll notice that the drug isn't being marketed as esketamine, its chemical name. Instead, Janssen (the pharmaceutical company that developed it) is marketing it under the trade name Spravato.

Q. So what’s all the controversy about?

A. Some researchers are not convinced that the evidence base for esketamine’s effectiveness has been readily established, therefore they believe that its approval as an antidepressant drug is premature. Others worry about esketamine’s addictive properties. Obviously, the FDA believes there was sufficient evidence to approve esketamine as an antidepressant and that its potential for abuse can be mitigated with the controls required. While many doctors are very excited about esketamine's approval, others disapprove.

Q. How has the FDA responded to concerns about its approval of esketamine?

A. By including a "black box" warning on the packaging, described this way in their press release approving the drug:

The Spravato labeling contains a Boxed Warning that cautions that patients are at risk for sedation and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug. . . . Additionally, Spravato must be dispensed with a patient Medication Guide that outlines the drug’s uses and risks. 

Q. Closing thoughts?

A. Even with the FDA approval of esketamine nasal spray for treatment-resistant depression, more research on both esketamine and ketamine as antidepressants is clearly needed. More generally, whether you are excited or skeptical about the FDA approving esketamine will likely be informed by your broader perspective on the underlying causes of depressed mood (i.e., is it mainly a problem of neurochemistry or is it more attributable to upbringing, environmental circumstances, irrational thinking, socioeconomic inequality, or other psychosocial causes?).  

For more on esketamine, see the FDA news release.