What is esketamine?

Following FDA approval of esketamine as a nasal spray to address otherwise untreatable cases of depression, Michael Thase, a professor of psychiatry at Penn Medicine, explains what it is and how it came to be.

Man sits down with doctor to discuss mental health

There’s a new drug on the antidepressant scene: Spravato (generic name: esketamine).

If the name sounds familiar, it’s for good reason—the drug is a relative of ketamine, an anesthetic drug that has a checkered history because of its notoriety as the recreational drug “Special K.” The FDA approved the drug in early March for treatment of people with treatment-resistant depression, which may include as many as one-third of people who seek medical treatment of depression.

In a conversation with Penn Today, Michael Thase, a professor of psychiatry at the Perelman School of Medicine and the Corporal Michael J. Crescenz Veterans Affairs Medical Center, explains more about what esketamine is, the serendipity of its discovery, and what else is happening in the world of antidepressant research.


What is esketamine, and what prompted its study for treating depression?

The antidepressant effects of ketamine, the parent drug, were first observed in the late 1990s and were completely unexpected. Because a subanesthetic dose of ketamine can cause symptoms that are similar to psychosis (i.e., euphoria, illusions, dissociations, and, rarely, hallucinations), it was used in experiments to see if certain new medications might protect against ketamine-induced symptoms. Some people noticed that their symptoms of depression lifted later that day or the next morning, i.e., long after the intoxicating effects of the drug had faded. It took about 10 years from this serendipitous observation until the first proper study was completed. And then it took almost 10 more years to commercialize these observations as the results of additional studies of ketamine infusion were trickling in. We went from intravenous infusions of a generic anesthetic drug, ketamine, to then developing the closely related drug, esketamine, which is taken intranasally.

Although 20 years is a long time, that’s about as fast as it gets in the U.S. pharmaceutical industry—from discovery through three phases of study on through FDA approval. And, during the time that esketamine was in development, confidence that intravenous ketamine offered a powerful alternative treatment for some depressed people grew steadily, and infusion therapy centers—ketamine clinics—began to spring up around the U.S. There are several such centers in the Greater Philadelphia Area. Esketamine is not a metabolite of ketamine, it’s what’s called a stereoisomer, and I’ll explain the difference.

In the laboratory, some drugs exist as a mixture of chemical crystals that are mirror-image forms of each other. Such a drug is called a racemic mixture of these ‘stereoisomers’; one half of the crystals reflect light to the left—the S form—and one half to the right—the R form. Despite otherwise being identical, this property, called chirality, can determine the potency and therapeutic activity of the drug. The best example from recent memory for psychiatry is the drug citalopram, which came to the U.S. as the fifth member of the class of antidepressants that includes Prozac. Citalopram turned out to be an OK drug, but a few years later, a “new” drug—known as escitalopram (Lexapro)—consisting only of the left-reflecting crystals, came to the U.S. and had much greater success. Indeed, this particular stereoisomer drug eventually became the most widely prescribed member of that class of medication. So, there’s one practical example of how a stereoisomer can actually be a better option than the parent drug. Ketamine, which has been approved by the FDA for use as an anesthetic for more than 30 years, is likewise a racemic drug. The S-enantiomer, now called esketamine, is somewhat more potent than the R-enantiomer, and the patent for development as an antidepressant was available to Janssen Pharmaceuticals, which is a subsidiary of Johnson & Johnson. Spravato differs from generic ketamine in another important way. When used as an anesthetic, ketamine is administered through an intravenous line, which also is how it was administered in most of the early studies in depression. However, intravenous infusion is not a particularly user-friendly model of delivery for psychiatric practice, which is predominantly outpatient-based, so esketamine was developed and tested as a nasal spray.

Spravato is the only drug approved for the treatment of depression that is delivered as a nasal spray. The treatment will be provided at registered centers and, although it only takes about four to five minutes to dose the drug, each treatment session will take at least two hours so that the effects can be monitored to ensure safety. Because the antidepressant dose of intranasal esketamDine—84 mg for most people—has some anesthetic effects and might affect judgment or perception, people won’t be able to drive the rest of the day after a treatment. Also, because Spravato shares the same abuse liability as ketamine, the drug is classified as a controlled substance according to the Drug Enforcement Agency, Schedule III, and will be kept at the treatment center, not purchased at retail pharmacies. All of the newer antidepressants introduced over the prior 30 years were variations or slight modifications of the existing classes of medications, such as Prozac [fluoxetine]. This adds to the novelty of Spravato. Every other important new idea to try to develop antidepressants that work differently than the standard way failed. They failed. And Spravado by contrast was close to a sure thing because the effects were so clearly known with ketamine as an infusion. But to see them with esketamine intranasal delivery is pretty much a sure thing.

Although, as the first member of a new class of medications, there’s still a lot of work to be done on Spravado.

Is there any promise for a pill form of this?

Not with this exact mechanism. [But] this new mechanism is working through the NMDA receptor of the glutamate system, which does open the door to all sorts of possibilities. Ketamine, because its antidepressant effects were discovered accidentally, carries with it all the baggage that comes with an accidental discovery. Meaning the drug has many effects. Beyond the potential for effects on thinking and perception, it can raise your blood pressure for the first hour or two after you take it, and even at the sub-anesthetic doses it can make some people drowsy and some dizzy. But this particular mechanism may still be relevant for newer, more selective drugs, and there’s great promise that a more selective drug can be developed that won’t have the FDA classification of being a potentially habit-forming drug. Likewise, novel drugs that can be taken by mouth may be discovered that work through effects on the NMDA receptor.

Is there much precedent for having to undergo these therapies in an office with a doctor?

Not in psychiatry. But in other fields, there are infusion therapies for people who have cancer and there are also infusion therapies for certain kinds of autoimmune diseases. There are other areas of therapy where people do this.

And of course, we all use the same-day surgery procedure, or [procedures like] a colonoscopy. But this is new to psychiatry, and different practices will have to figure out how to do it. Because the day you have a treatment, you need to be in the office for two hours and you will not be allowed to drive yourself home afterwards.

And to be extra clear, this is for people who are resistant to existing treatments?

That’s right. It’s approved as an add-on treatment for people who have not responded to at least two adequate treatment trials. These are folks with more longstanding, yet often disabling depressive illnesses who, modern therapies, specifically the modern classes of antidepressants, have not done the job for them. In practice, people will try four or five or even more standard therapies before they come to this.

Are there other new developments happening with antidepressants?

Oh yes, many. Some of which target entirely different neurochemical mechanisms, including some that are indirectly related to the ways ketamine and esketamine works. There’s one that’s related to a particular reproductive hormone in women, allopregnanolone, and others that have been tested through opiate pathways, so there are all sorts of different treatments [being researched].

So, this doesn’t need to be a miracle solution?

It is not a miracle solution. But it’s a wonderful thing if you get a nice response to it if your depression is debilitating—a life-altering illness. Having another treatment that can help many long-suffering people is a good thing. Has there been any refinement of modern drugs since they were first introduced? That’s what’s happened between about 2000 and 2014, with four or five different refinement drugs of SSRIs that have come out, but society has decided these refinements do not often justify the extra cost compared to a generic drug, and typically we don’t use those refinement drugs until courses of newer medications have been tried.


They’re still patented, so they cost more. And the people that manage healthcare benefits have decided they’re not worth the extra cost, and mostly generic, inexpensive drugs have been tried.