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Dr Banov Discusses Esketamine's Role As a Rapid Response Treatment

Michael Banov, MD explains the mechanism of action for esketamine, pros and cons of use for treating major depressive disorder, and highlights questions that remain.
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Transcript:

Dr. Michael Banov:  Hi, I'm Michael Banov. I'm a board certified psychiatrist and the Medical Director of Psych Atlanta and Psych Atlanta Research Center in Atlanta, Georgia. I'm also a clinical Associate Professor at the Medical College of Georgia.

Today, what I'd like to talk about is Spravato, also known as esketamine, and what is its place in the treatment landscape.

Esketamine was approved in 2019 for treatment‑resistant depression. It's an important paradigm shift in the treatment of depression for so many reasons.

It is an intranasal form of esketamine. Esketamine is an isomer, or S(+) enantiomer of ketamine, a medication approved by the US Food and Drug Administration, or FDA, for anesthesia and pain management.

Ketamine has been used over the last few decades as an off‑label treatment for depression, but is not approved by the FDA for that indication.

There remain a lot of questions about ketamine's safety and effectiveness, as well as who can benefit from the medication, and how to maintain any benefits that may be seen, since the therapeutic effects seem to wear off quickly.

There are a lot of double‑blind, randomized studies with ketamine and depression and other mood disorders, but they have not been conducted with any consistency to be able to replicate the findings, and have not undergone the scrutiny given to FDA‑approved therapies.

What makes esketamine so unique?

First, its mechanism of action. Keep in mind that the true mechanism of action of all antidepressants are not fully understood. Most all antidepressants in the market target serotonin, dopamine, or norepinephrine receptors or some combination.

Esketamine non‑competitively binds to and blocks the N‑methyl‑D‑aspartate, or also known as MDMA receptor. Drugs that block the NMDA receptor reduces pain perception, it can induce sedation, and it can produce a dissociative anesthetic experience.

Why the S(+) enantiomer of ketamine?

The S(+) enantiomer or esketamine has three to four times more affinity for the NMDA receptor than the R(+) enantiomer. It allows for less of the drug to be administered to produce an antidepressant effect.

The hope was also, with less of the medicine administered, perhaps some of the risks of the racemic mixture, ketamine, could be reduced. Maybe less dissociation and other side effects.

However, since there are no comparator studies, we don't know whether esketamine actually has fewer side effects than ketamine. We don't know if it's safer, both short and long term. We don't know if it's less or more effective, or if there's certain mood and anxiety disorders that may respond to one better than another.

We know that esketamine affects glutamate in the brain. It's an important excitatory neurotransmitter. It's responsible for signaling between nerve cells, and it plays a role in mood, anxiety, memory, and learning. Esketamine appears to have an effect on brain plasticity, to increase neuronal dendritic growth and improved synaptogenesis.

If you really want to get granular, it stimulates the production of brain‑derived neurotrophic factor, or BDNF. It activates the mammalian target of rapamycin, or mTOR, but whether some or any of these medication effects explain some or all the benefits is just unclear at this time. What we can say, it doesn't work like the other antidepressants that we have.

What else is unique about esketamine?

The indications. esketamine is FDA‑approved for treatment‑resistant depression, and as of 2020, approved for patients with depression with suicidal ideation and behavior.

There are very few therapies approved for treatment‑resistant depression, which can affect up to 30 percent of those with major depressive disorder, and is associated with significant emotional, social, and economic burden.

In patients with suicidal ideation and depression, who are typically more difficult to treat and they're generally excluded in clinical trials for new medications.

Keep in mind that although this doesn't mean it treats suicidal ideation and behavior ‑‑ although it may, that remains to be studied ‑‑ but it does help treat depression in those with suicidal thoughts or actions.

Third, the administration of esketamine is unusual. It has to be given in a treatment center that's certified, by a certified staff that is trained in giving this treatment.

Also, there are very clear guidelines on how much to take, how frequently to take it, and there's standardized training for health care providers on how to administer it safely. It's through a program called Risk Mitigation and Evaluation Strategies, or REMS.

REMS make sure that the medicine is given for the right indications, that patients and providers understand the risks associated with the treatment. REMS monitors for new adverse effects that may have not been seen in the clinical trials, or for a change in the frequency and severity of adverse effects that were seen in the clinical trials.

Another aspect of esketamine, the side effects. We know that most oral antidepressants share similar side effects, such as sexual problems, weight gain.

Esketamine can have some unusual side effects, including extreme sedation, rapid elevation of blood pressure, nausea, and dissociation.

With oral antidepressants, there's medicine in your system 24/7. With esketamine, the medicine has a bi‑phasic, short half‑life, with a rapid decline in concentration within 2 to 4 hours, and a terminal half‑life of 7 to 12 hours. In short, typically, the side effects resolve quickly after administration.

The most commonly reported side effects in short‑term clinical trials are nausea, dizziness, dissociation, headache, and vertigo.

Most of the adverse events were mild to moderate in severity and resolved the same day following dosing.

In all three studies with esketamine, the dissociative symptoms were seen shortly after dosing, which peaked at 40 minutes, and resolved in one‑and‑a‑half hours.

The dissociation, although considered an adverse effect, can be pleasant, and even therapeutic for some, although for others it can be uncomfortable or disturbing. Some even argue that the dissociation may be a part or even necessary for the therapeutic effects, although this remains to be proven.

The set and setting for giving esketamine is very important to minimize the negative effects of dissociation. This means a quiet, safe, and comfortable place.

Elevations of blood pressure, increased intracerebral pressure, sedation, or uncomfortable dissociation can have very serious consequences, which is why all patients must be monitored by a health care provider for at least two hours during administration. Fortunately, esketamine has a short half‑life, so typically, these effects, if they do occur, also quickly resolve a few hours after dosing.

Another difference, antidepressants typically take four to six weeks to work, and sometimes longer if you need to increase the dose. Although the primary endpoint in the approval studies was the change of the MADRS at the end of 28 days, analysis of secondary endpoints showed a significant number of subjects had improvement within 24 hours following a single dose.

Although esketamine has been shown to safe, effective, and certainly a novel form of treatment, it's not without its concerns. Only one of the three short‑term trials in patients with treatment depression were positive.

Now, the counter argument to this is, this was a difficult‑to‑treat population, and the study design created a high bar to achieve statistical significance. For example, those in the trials had to stop their current antidepressant and start a new one at the same time they were starting either the esketamine or the placebo. Just changing the antidepressant will likely benefit some.

What about other downsides?

There are significant obstacles to getting esketamine treatment. An intranasal device that must be done in office creates some payment questions for third‑party payers. The cost of the medicine is high, and there's the added cost of paying for supervised administration.

Unfortunately, one of the unique attributes of this treatment is its speed of onset. Yet, ironically, it can take an unusually long time to get the medication approved for use by an insurance company. Also, there may be another access issue in finding a facility and provider nearby and in network, who can deliver the medication.

While there's long‑term data showing that those that respond are more likely to stay well if they continue to get esketamine every week or every other week, there are concerns about the durability of response, given that the positive effects of ketamine seem to dissipate quickly, and how long do you need to take it to stay well. Once a week, every other week? That's a big ask for patients, payers, and clinicians.

Where does this medicine fit into our treatment algorithm?

The obvious place would be someone intolerant or non‑responsive to oral antidepressants from at least two different classes, say an SSRI and an SNRI, perhaps failed augmentation strategies with second‑generation atypical antipsychotics, such as aripiprazole, brexpiprazole, lithium, thyroid, stimulants, maybe even adding additional antidepressants with different mechanisms of action.

Another place may be someone with depression with suicidal ideation, where time to treatment response is critical. Perhaps in patients who've been unable to tolerate antidepressants due to side effects, although currently, esketamine is only approved for those concurrently taking an oral antidepressant.

Hopefully, these obstacles to treatment can get worked out over time, because there's an important unmet need for the management of treatment‑resistant depression, which is taking an enormous toll on individuals suffering from treatment‑resistant depression, as well as their families, friends, employers, and society as a whole.

After a decade of oral antidepressant copycats and a noticeable lack of innovation in the pharmacologic management for this disabling condition, it's refreshing to see innovation and hope for those whose lives have been so impacted by this condition.