01. Ketamine and Esketamine: Foundations, Patient Selection, and Algorithm Placement

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Regulatory Differences Between Ketamine and Esketamine

Flavio Guzmán, M.D.: Let’s start with the basics. From a regulatory standpoint, how do ketamine and esketamine differ?

Samuel Wilkinson, M.D.: In the United States, esketamine has FDA approval for treatment-resistant depression, as well as for depression with suicidal ideation. Ketamine, on the other hand, does not have approval for any psychiatric illness.

This has significant implications for real-world use and clinical practice. Esketamine is subject to a strict drug safety program, called REMS, imposed by the FDA.

This program includes a number of safety features. For instance, clinics are prohibited from dispensing esketamine for home use, and they must ensure that patients do not drive on the days of treatment.

Racemic ketamine, by contrast, does not have any drug safety program. It is a bit like the Wild West, without strong regulatory control over how ketamine is prescribed for off-label psychiatric use.

Relative Efficacy: What Observational Data Do and Do Not Tell Us

Flavio Guzmán, M.D.: When it comes to efficacy, how do these two compare?

Samuel Wilkinson, M.D.: In my opinion, the jury is still out on the relative efficacy of ketamine versus esketamine. There have been a few observational studies analyzed, including one from my own clinic, and some have suggested that ketamine may be slightly more efficacious.

The problem with those studies, and with broader comparisons between ketamine and esketamine, is that in the real world, all else being equal, patients who receive ketamine tend to be wealthier than patients who receive esketamine.

Because wealth is an independent predictor of better health outcomes, it is not clear whether the slightly better outcomes seen in a few of these studies with ketamine are due to the treatment itself or to differences in the patient populations.

Durability of Response and the Challenge of Waning Effects

Flavio Guzmán, M.D.: One concern I often hear about esketamine is that the short-term effects tend to wane over weeks. In your view, does that pattern undermine how useful it is as an antidepressant in practice?

Samuel Wilkinson, M.D.: One of the limitations of esketamine, and probably of ketamine as well, is that the effects on average tend to wane over time without repeated exposure. It is a very intensive treatment.

The most recent data, published in the fall of 2025, suggest that for most patients receiving esketamine, the most common frequency after the first two months of treatment is weekly. That was a bit of a surprise to me.

At our clinic, we try to spread out the frequency of treatments further, aiming for every three or four weeks after the initial month or two. That is a problem because it is very inconvenient for patients to come in that frequently.

So an open question is: how can we make this longer lasting?

In terms of its rapid-acting nature, I think it still has a lot to offer compared to traditional antidepressants. Not every patient receives substantial benefit after just one to two doses — most who benefit need three, four, five, or six doses — but it does offer a substantial improvement over existing antidepressants.

Safety: Regulatory Framework Versus Biochemical Risk

Flavio Guzmán, M.D.: Moving to safety, could you please compare them?

Samuel Wilkinson, M.D.: Practically, esketamine is safer than ketamine, but only because of the regulatory framework. From a biochemical perspective, there is not really much difference in safety. Because there are strict controls on the use of esketamine, it is overall safer.

A number of sentinel events are starting to emerge. The most famous was Matthew Perry’s death. At the time I am recording this interview, just yesterday the “ketamine queen,” who was the source of ketamine for Matthew Perry’s death, was sentenced to 15 years in prison.

There is very much an unregulated aspect to the use of ketamine for psychiatric illness, especially at-home ketamine use. That is not the direction we should be going as a field.

From a practical standpoint, esketamine is fairly limited in dosing. Ketamine as a chemical is neurotoxic at high doses. We do not know exactly where that threshold is — it seems to be a combination of dose, frequency of exposure, and cumulative exposure.

The doses and frequencies used within the REMS framework for esketamine are, I think, quite safe. By contrast, if someone is receiving very high doses of ketamine on a daily basis for even just a couple of months, what we know from the animal literature suggests that could lead to neurotoxic effects.

Abuse Liability and the Real-World Implications

Flavio Guzmán, M.D.: What about abuse liability?

Samuel Wilkinson, M.D.: There is good data on this from Richard Dart, who runs the Rocky Mountain Poison Data Center in Colorado. He has published on rates of abuse of both ketamine and esketamine in the United States.

There was essentially no rate of abuse of esketamine. The rate of abuse of ketamine is steadily increasing.

This all has to do with the regulatory framework. By statute, you are not allowed to prescribe esketamine for home use, and that dramatically diminishes the chance of abuse. It is also practically very difficult to abuse esketamine in the form it comes in.

The company has designed it to come in rather bulky containers, so to store or stash an abusable amount of esketamine, you would need a whole backpack full of dispensing cartridges.

Because of the regulatory framework, there is no question that esketamine has a safer abuse liability profile.

Reconciling the Esketamine Suicidality Data

Flavio Guzmán, M.D.: Here’s a question that has generated some debate. Esketamine is FDA-approved for depression with acute suicidal ideation, and yet a recent meta-analysis by Fountoulakis — excuse me for the mispronunciation — found minimal effects on suicidality. From the perspective of a clinician, how should we reconcile these conflicting messages?

Samuel Wilkinson, M.D.: It is important to understand how these trials were run and the natural course of acute suicidal ideation. When patients come into the hospital with acute suicidal ideation — and this is the way these trials were run — the vast majority are going to get better.

All those patients in the trials, or nearly all, improved quickly, including the patients on “placebo.” Those patients received really good care and got better with their acute suicidal ideation.

So it is not that esketamine did not work. It is that it was hard to show an improvement beyond really good standard of care.

It is true that there were not significant differences between the esketamine group and the placebo group. But what a lot of people do not realize is that the “placebo group” received really, really good care and got better, as most patients do under such conditions.

Defining Treatment-Resistant Depression in Practice

Flavio Guzmán, M.D.: Let’s shift to patient selection. When you’re deciding whether a patient is a candidate for ketamine or esketamine, how do you define treatment-resistant depression?

Samuel Wilkinson, M.D.: Treatment-resistant depression is most commonly defined as a patient with significant depression who has not responded satisfactorily to two or more antidepressant trials of adequate dose and duration. This is most commonly enforced by insurance companies when deciding whether to approve a patient for esketamine treatment.

Other patient factors I consider when thinking about offering ketamine or esketamine include:

• Severity. If a patient is not very severe, ketamine or esketamine probably is not warranted.
• Abuse liability. Even when treatment is delivered in a clinic rather than via take-home doses — which is how I think it should be done — patients with active substance use disorder pose a challenge. You do not want them to develop an appetite, so to speak, for ketamine and then seek it on the street, introducing another problem.

For patients with a strong personal history of substance abuse or substance use disorder, I am very wary about offering these treatments. It is a difficult decision because many of these patients need help, but the first principle of medicine is to do no harm.

Our clinic was fortunate to be part of a large comparative study comparing ketamine to ECT, which for a long time has been considered the gold standard for difficult and treatment-resistant depression.

This study showed, at least in a sample that was primarily outpatients with moderate to severe depression, that ketamine was as good as ECT. Another study conducted around the same time in Europe showed slightly different results — the difference being that it was an exclusively inpatient study.

When deciding between ketamine and ECT, I consider:

• Severity and setting. For inpatients, I tend to favor ECT. For outpatients, I tend to favor ketamine.
• Age. For patients 65 or 70 and older, there is still pretty good data that ECT may be the way to go. For younger patients, especially under 50, ketamine may be preferable.
• Substance use history. With a significant personal history of substance use disorder, I feel more comfortable with ECT.
• Psychotic depression. Although not that common, ECT continues to be the gold standard for patients with a psychotic form of depression.

Predictors of Response to Ketamine and Esketamine

Flavio Guzmán, M.D.: Are there patient characteristics that predict a better response to these treatments?

Samuel Wilkinson, M.D.: There really are not new factors that predict response to ketamine that do not also predict response to antidepressant treatment generally.

Patients who develop depression at an earlier onset have a worse prognosis. If someone develops depression at 17 or 18, and that interferes with their ability to go to college or get a job after high school, it affects a critical period of skill and ability development that can have lifelong consequences.

So earlier age of onset tends to negatively affect chances of recovery, whether the treatment is fluoxetine, ketamine, or anything else.

Earlier reports suggested that ketamine was as effective for anxious depression as for depression without anxiety. The most recent reports I am familiar with suggest that may not be the case.

The presence of anxiety in depression has long been a harbinger of more difficult-to-treat illness. Some earlier reports with ketamine had suggested this might not apply, but unfortunately that is not bearing out the way we had hoped.

Other factors that predict response, generally speaking:

• Good interepisode functioning
• Strong social support
• Being married or having a family

These are good prognostic factors for ketamine and also for depression treatment in general.

Contraindications and Cautions (Aneurysm, AVM, Substance Use)

Flavio Guzmán, M.D.: And on the other side of that — are there patients who clearly should not receive ketamine or esketamine? And what contraindications do you watch for?

Samuel Wilkinson, M.D.: According to the FDA label for esketamine, aneurysm and arteriovenous malformation are contraindications. I do not think these are absolute contraindications — you just need to be very careful with these conditions.

I say this in the context of my experience with ECT. Both ketamine and ECT can cause short-term increases in blood pressure and heart rate, but the increase is generally much more pronounced with ECT.

There have been a handful of reports examining the risk of ECT in patients with either aneurysms or arteriovenous malformations. As far as I am aware, there is not a single case report where ECT caused a rupture of an aneurysm or AVM, despite blood pressures sometimes rising very high — systolic pressures above 200, even 250, if only for a few minutes.

ECT causes a much more pronounced increase in blood pressure than ketamine. So these contraindications that the FDA imposed on esketamine are really theoretical. There has never been a documented case of ketamine causing an aneurysmal rupture or AVM rupture.

Other contraindications include substance use disorder. It is not written on the esketamine label, but I am very wary of providing esketamine or ketamine to people with active substance use disorder.

If they are recently in recovery, I am also hesitant. If it has been several years of sustained remission from a substance use disorder, I am much more open to it, but it still gives me pause.

Where Ketamine and Esketamine Fit in the Treatment Algorithm

Flavio Guzmán, M.D.: Moving to how this fits into a broader treatment strategy — where would you position esketamine in the algorithm? Is this the first option, or does it come in later as augmentation for treatment-resistant cases?

Samuel Wilkinson, M.D.: I definitely do not think ketamine or esketamine should be a first-line treatment for general depression. Once patients fail two, three, or four adequate trials of antidepressant therapy, I think it is very reasonable to turn to ketamine or esketamine.