Ketamine for Depression Faces Its Biggest Test Yet , John Watson, 04/04/2019

Ketamine for Depression Faces Its Biggest Test Yet

John Watson

April 04, 2019

One of the more unexpected stories from this past decade of psychiatric research has been the journey of ketamine from illicit drug to a promising therapy for treatment-resistant depression. Yet, even as its reputation has been burnished by accounts of patients experiencing dramatic responses to short-term therapy, ketamine was noticeably lacking in large-scale trials necessary to shift it further still, from an experimental treatment to an established intervention.

In 2017, investigators sought to address this gap by initiating the ELEctroconvulsive therapy (ECT) vs. Ketamine in patients with Treatment-resistant Depression (ELEKT-D) trial.[1] Sponsored by the Cleveland Clinic and led by their Vice-Chair for Research, Amit Anand, MD, ELEKT-D will eventually enroll 400 patients with treatment-resistant depression who will be randomized to receive either ECT (thrice weekly) or IV ketamine (twice weekly) for 3-5 weeks. In its sheer scale and follow-up duration, ELEKT-D will be well equipped to answer questions about ketamine’s safety and efficacy in this population unlike any study that came before it.

Medscape spoke with ELEKT-D investigator Donald Malone, Jr., MD, Cleveland Clinic’s chair of the Center for Behavioral Health, about this ongoing trial and what ketamine therapy may look like in the near future.

The State of the Science

Medscape: What have the past few years of ketamine research shown us in terms of the conditions in which it has the most potential?

Malone: There have been issues with the data, even with blinded studies. We have to be honest that it’s hard to blind yourself to ketamine if you compare it to something like midazolam. Most patients can probably tell the difference.

There have been publications that have come out over time that suggest efficacy, but I think the only real data exist with both unipolar and bipolar depression. There are other potential uses out there, such as for pain, post-traumatic stress disorder, or obsessive-compulsive disorder, but I think those data are meager for the most part. It’s probably a little bit better in pain than the other two, but still, it’s not that robust.

Medscape: Even though data are limited and from short-term studies, the effect of ketamine in depression has been described as fairly dramatic. What does that tell us about its potential efficacy?

Malone: I don’t think you’d get an argument from very many people that ketamine clearly has antidepressant properties in the acute situation. Many people feel a release of depressive symptoms with the acute use of ketamine, but this effect tends to be transient in many of these studies.

It leaves open several questions. Is long-term ketamine use successful? Can you maintain response with longer-term ketamine use, or is that problematic? Are there any longer-term side effects to ketamine? Given that it’s excitotoxic, is there a critical amount of ketamine that can create negative consequences to the brain? Those questions really remain to be answered.

Medscape: Have these short-term studies uncovered any specific safety concerns that warrant immediate attention?

Malone: You have to be a bit careful in that you can have dissociation. That’s not always a negative but certainly it’s a concern.

But overall, it seems to be well tolerated and relatively safe, though in our trial we’re using it at very low, sub-anesthetic doses (0.5 mg/kg).

The other question is, how addictive is it? It certainly has been known as a drug of abuse and we always need to be cautious when we’re using potentially addictive psychoactive drugs to treat mental health conditions. It does have effects on opiate receptors. We always say it works because it’s an N-methyl-D-aspartate antagonist, but that’s not necessarily true. It may be effective because of its opiate-like properties as well.


Medscape: What led to the Cleveland Clinic becoming involved in bringing ketamine research in house on such a large scale?

Malone: We do a lot of ECT and have been involved in studies with deep brain stimulation, so we have a large population of patients that tends to migrate to us that is highly refractory. We’re always looking for what would be a value, which we have found ketamine to be in certain patients.

That being said, it’s not something that we jump to very quickly. We’ve really reserved it for highly refractory patients who have not responded to other things, including ECT. They really have to fail adequate medication trials and not just cursory one-medication trials, but combination therapies, etc.

Our population of patients is not the typical one that you would see in the general community, so we’re always looking for these extra things to do, but we do them very carefully. That was what generated our interest in doing a large-scale trial looking at ketamine in these highly refractory patients who are being referred for ECT. It’s a four-site study in which we’re the primary site. It’s going to enroll a large enough number of patients that it will allow us to look at how these patients do both in the shorter and longer term.

Medscape: When do you expect that to yield data?

Malone: It has about 2 more years to run. We’re about halfway through recruiting patients, so it may close a little bit sooner than that, but there’s still a ways to go. Again, when you’re looking at these highly refractory patients, they’re not everywhere.

Medscape: How does ELEKT-D break new ground compared with the studies that came before?

Malone: Number one, we’re comparing it to what has been for many years the gold standard for refractory depression, a very powerful treatment already.

Then you are following patients over time—not just for a week or two, but for a year. You’re really going to see what happens longer-term. You’re going to help determine whether periodic maintenance treatments are efficacious, and you’re also looking very carefully for any toxicity and adverse events that will happen over the course of this treatment.

I think it’s very important that this be done carefully and really run by psychiatrists, because you’re using it for mental health conditions. It’s very important that you get the right diagnosis and that you follow carefully with appropriate monitoring, and look for efficacy with well-defined scales and other means of assessing objectively what patients are experiencing.

How Will Ketamine Be Administered Going Forward?

Medscape: The US Food and Drug Administration just approved the intranasal form of ketamine, esketamine, for treatment-resistant depression. They’ve stipulated that it be administered on site, with patients monitored for 2 hours thereafter. Do you think the data they based this decision on are persuasive, and are you comfortable with the suggested administration?

Malone: I do believe that the data are sufficient to justify approval. The guidelines put in place appear reasonable and quite consistent with how we provide IV ketamine. The wild card in all of this is how insurers decide to cover these treatments, and ultimately the cost to insurer and patient.

Medscape: Do you think this opens the door to patients eventually being prescribed ketamine directly through their pharmacies, without the stipulation that it be administered in-office?

Malone: If you formulate it for intranasal use, I guess you can give it to the patient to take home right now, which in my mind is highly risky. Is there a diversion of it for illegal use? It’s just fraught with all kinds of potential problems. I think if it’s used in a certain way under supervision, then it’s quite reasonable as a medication. Then qualified psychiatrists would be able to offer that. But I don’t know that sending people home with vials of ketamine is reasonable in any way.

Medscape: There’s been a lot of attention paid recently to the surge in ketamine infusion clinics offering this as an off-label treatment for multiple indications. Among the many criticisms waged against these clinics is that many do not use psychiatrists or others specialized in treating psychiatric conditions. But do you think these clinics are going away any time soon?

Malone: As a scientist, I can only argue for caution, care, and adequate study. These are very vulnerable patients. They’re willing to try anything. They’re suffering, they have high suicide rates. There’s certainly a tremendous need for effective treatments in these individuals.

It’s not surprising that they would latch on to anything that would have some ray of hope, especially if the acute intervention results in an improvement in mood the first time. People are probably ready to sign up.

But again, we don’t really understand the consequences of that. How should we give it and for how long? What are the doses we should give? What does maintenance treatment look like? What happens if it stops working? We just don’t have answers to those questions. Certainly I think it’s a risk to put it in the hands of groups that aren’t used to treating these highly refractory patients.

Medscape: One of the secondary advantages of ELEKT-D would seem to be in bringing ketamine back under the umbrella of established, rigidly performed science and out of the hands of some of the perhaps less scrupulous actors in this space.

Malone: I’m not saying that those individuals don’t mean well. I don’t know. I’m not going to attribute meaning.

But I think, absolutely, the state of the science right now with IV ketamine would suggest caution and that it’d be kept in the hands of those who are willing to study it and are able to manage these patients.

These patients don’t just need ketamine. They’ve been sick for a long time, typically and very severely. They need to have suicidality monitored and to typically be in some other forms of psychotherapeutic treatment. They typically need more than just a quick dose of ketamine.

I think that to do it outside of a program that is able to do those things and accommodate the needs of those patients is frankly not good practice and potentially dangerous. There was a recent editorial from Dr Charles Nemeroff in the American Journal of Psychiatry, where he outlined similar concerns,[2] as others have before him.

Ketamine is definitely a potential treatment that actually has some evidence behind it, and which does provide some cause for hope that it will turn out to be an effective treatment for some or many of these patients. We just don’t know that yet, so that’s why we’re studying it. And it’s important to do it right.

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  1. Mathew SJ, Wilkinson ST, Altinay M, et al. ELEctroconvulsive therapy (ECT) vs. ketamine in patients with treatment-resistant depression: the ELEKT-D study protocol. Contemp Clin Trials. 2019;77:19-26. Source
  2. Nemeroff CB. Ketamine: Quo vadis? Am J Psychiatry. 2018;175:297-299. Source