Dr. Perry Wilson: In the year 2000, seven individuals suffering from major depression were part of a crossover study which suggested that ketamine was superior to placebo in terms of controlling depressive symptoms. Research in the area has grown rapidly with data suggesting that even one-time doses of the dissociative anesthetic may have significant benefit in individuals with mood disorders. While most studies have been small, the sheer potency of the effect bears discussion and consideration as to whether there's a place for ketamine in clinical practice. To discuss the use of ketamine and mood disorders, I'm joined today by Dr. Gerard Sanacora.

Dr. Sanacora is a Professor of Psychiatry at the Yale School of Medicine and the director of the Yale Depression Research Program. He's an internationally recognized expert on the use of ketamine in psychiatry, both on a psychiatric and neurobiological level. Dr. Sanacora, thanks for joining me on Doc 2 Doc.

Dr. Gerard Sanacora: Thank you, Dr. Wilson. Glad to be here.

Dr. Perry Wilson: I find this to be just an incredible area of medical research because you have what is essentially a very old drug — a drug with some abuse potential, obviously — that people weren't really considering in a psychiatric role at all. How did ketamine get its start in this area?

Dr. Gerard Sanacora: It's very interesting. As you said, several different factors coming together to make this a very interesting story. The use of ketamine actually goes back quite a ways for psychiatric purposes. There were some early studies going back into the 70s, at least, looking at augmenting psychotherapy with ketamine, but that research really didn't carry on far and sort of the trail ended.

It really picked up again in the late 1990s when there was increasing evidence suggesting that the glutamatergic neurotransmitter system could play a prominent role in the pathophysiology of mood disorders and depression. That got people interested in looking at glutamatergic drugs and how that may influence or potentially have some clinical benefit in depression. As you mentioned, there was the small study done here at Yale by John Krystal, Rob Berman, Dennis Charney, and others that looked at the ability of ketamine to have antidepressant-like effects. As you mentioned, that study showed very robust, very rapid antidepressant effects, and I think it really was an example of playing in the right sandbox. There wasn't so much a specific idea that this was going to have a rapid antidepressant-like effect, but the investigators at the time were smart enough to know what the surrounding research was and started looking in this area.

Dr. Perry Wilson: Ketamine is a drug that has been used for recreational purposes. It's a potential drug of abuse. It goes by the street name of Special K, amongst others. Can you give us a sense of what's the difference in terms of either dosage or usage or effects of sort of the street Special K and what people are getting in these clinical studies?

Dr. Gerard Sanacora: Ketamine, its primary use and what its indication is by the FDA, is the use as an anesthetic. It's used very commonly in pediatric anesthesia. It's used in the emergency rooms quite a bit. If you give enough ketamine, you can put somebody to sleep and take their tonsils out if you want. But at lower doses, it has more of a dissociative effect, effects on cognition and perception that can be quite pronounced before you actually get to the anesthetic doses.

People that are using it for abuse tend to use it at what we call the "subanesthetic" doses. The thing that makes it complicated is that over time people can build up their tolerance to it to some extent, so they can start using higher and higher levels of this drug. But the tricky part is if you use too much of it, it's an anesthetic, so it really is a kind of limited range that it can be used at. It's also really complicated because most people that are abusing it are not using it intravenously. They're either taking it orally, or in some way, inhaling it. It's really a little difficult to get the exact dose equivalents in what's being used clinically versus what's being used in the street.

In general, the doses that we're using clinically is a dose of 0.5 milligrams per kilogram, which is what was used in the original study, and it's a dose that is clearly subanesthetic. It's not a dose that puts any of our patients into an anesthetic state, but varies in how much it actually affects their cognition and perception.

Dr. Perry Wilson: Yeah, give us a sense. What do they feel when they are sitting there getting this drug?

Dr. Gerard Sanacora: For most people getting that standard dose, they do start to feel… the first thing is they start to have an altered sense of some of their perceptions, sense of hearing could change some, sense of vision can change some, so it's not uncommon for people to say they have a heightened sense of hearing. They may say that they're hearing things that they normally wouldn't hear such as somebody writing on a piece of paper, actually hearing the pen on the paper. Vision is somewhat altered, so people quite frequently say, as somebody will walk across the room, they will not necessarily see the smooth movement. They'll see sort of people at different points in time without seeing it move smoothly. But there's a variety of perceptual things. Sometimes there's color changes, things looking a little different than they normally do. But it varies a fair amount from patient to patient.

Dr. Perry Wilson: I want to try to tie the observed treatment effect, so the benefit in depressive symptoms, to mechanism of action a little bit here. You talked about the glutamatergic system. I wonder, also, if we can even take a step back and look at this from maybe a more psychiatric point of view and the dissociative symptoms or dissociative effect that the drug has. Do you think that this is just sheer neurotransmitter chemistry going on here or is there something about taking a depressed individual and sort of removing them from their own body for a time that has some therapeutic effect?

Dr. Gerard Sanacora: I think the answer is both. I think that there's very clear evidence of a true drug-specific neurobiological effect, probably having effects more immediately on the glutamatergic system, but downstream effects, modulating neuroplasticity and actually some brain architecture, actual changes in the way the neurons are communicating with each other. But I think with any of our treatments in psychiatry, in any branch of medicine, there is a large, non-specific effect that you get from any type of treatment. And this is a pretty robust treatment, a lot of interaction with the providers, the doctors, the nurses. A drug that has a pretty big effect, so it's hard to confuse it with a placebo. You know you took something.

Dr. Perry Wilson: Right.

Dr. Gerard Sanacora: I think this is probably a combination of both and there is a lot of hope that comes with this and a lot of other non-specific effects. I think this may be an ideal situation where there's synergy, where if you're actually having changes in brain structure and you're infusing some of these other non-specific effects, it could be partially why we're getting such robust benefits.

Dr. Perry Wilson: I should point out in terms of the placebo effect, it’s hard to mask that you're getting ketamine, but there's been at least one study I saw that used midazolam, I think, as an active comparator so the patient certainly would have felt a bit woozy and still saw this much more profound effect on the ketamine side.

Dr. Gerard Sanacora: There are now several studies using midazolam as an effect, and all of them have shown ketamine to still have an effect. You do see somewhat of an effect with midazolam, but ketamine has always shown a superior effect over that.

Dr. Perry Wilson: What's the acute period of time that you're under ketamine's effect? How long would you tell a patient, "Don't drive a car," for example? Then after a single dose, how long do you see effects in terms of depressive symptoms?

Dr. Gerard Sanacora: Again, I'll talk about sort of the standard dosing because people are using different dosing regimens. But for the standard 0.5 milligrams per kilogram given over 40 minutes intravenously — which is, I think, what most commonly is being used and definitely what has been reported most in the literature — the effects usually last a little bit beyond the time that the infusion is going, so the real acute effects. Not everybody feels it at all. Some people feel very minimal effects. But if they are going to feel something, it will usually come on within the first five to 10 minutes of starting the infusion and will probably last for about a half-hour after ending the infusion.

If it goes for 40 minutes, they're going to have these acute effects for somewhere about an hour, and then pretty rapidly diminishes after that time. In terms of driving, right now the strong recommendation — and this is the standard recommendation if you are getting an anesthetic agent — is not to drive until the next morning or 24 hours. I know there are several studies looking at this, doing some virtual driving studies, and seeing what that actual time is.

Dr. Perry Wilson: So at least a day that maybe there's something in your system that we would be concerned about, but the antidepressant effects are certainly longer than that, right? How long are we seeing from a single dose?

Dr. Gerard Sanacora: Exactly. Most of the studies that have looked at a single dose suggest that the effects even going out a week or even two weeks are still there, meaning that from baseline to those later time points, there's still evidence of improvement. [00:10:03] Most studies would suggest that the peak of the antidepressant effect hit within the first 72 hours, so if there is going to be a response, somewhere within the first four hours to 72 hours people get the greatest benefit, and then it gradually tends to dissipate over time.

Dr. Perry Wilson: This begs the question if we are to implement this type of treatment in clinical practice, we're not just going to be giving people one dose, right? We're going to be repeating doses. What's the current thinking on a schedule for this? Every couple weeks?

Dr. Gerard Sanacora: There really isn't great data to suggest. Probably the best data was a study that was done a few years ago that showed that dosing twice a week for a period of four weeks was quite effective, and there was no added benefit of dosing three times a week, so two times a week seemed to be just as good as three times a week, at least in initiating treatment.

Then following up on that, there's very, very little data that's available in terms of what long-term maintenance is. When we polled a large number of people that are doing this clinically, it seems to be that the average patient is returning about every three to five weeks, somewhere in there for a boost as a session. Now that being said, it is important to note that there is a subset of patients that just report having the treatment, either it be eight treatments, six treatments, or in some cases it's only a single treatment, and having a sustained response. But that's really the exception rather than the rule.

Dr. Perry Wilson: Now we have a new study sponsored by Janssen Pharmaceuticals looking at the S enantiomer of ketamine. It just came out recently. Give us the brief results there.

Dr. Gerard Sanacora: As I mentioned, we really don't have much what I would consider high-quality data, especially over longer-term use. We are now starting to see these studies rolling out — so work by Janssen, sponsored by Janssen — looking at what is effectively, which are phase III trials, is looking at the efficacy compared to placebo, and more importantly looking at the duration of effect over time. We are seeing data going out over a year with repeated dosing. That suggests that the S-ketamine can be given safely and maintain efficacy over that time with repeated dosing.

Dr. Perry Wilson: Let's talk about the patients that you might consider this for. You have a clinical trial that's recruiting patients right now that's randomizing to ketamine versus electroconvulsive therapies. These would be people with fairly refractory, severe depression. Is there any sense that people with more mild depression, people that might not get as much benefit from SSRIs as they would have liked could try this as an alterative therapy or is this just for the people who are the worst of the worst in terms of the symptoms?

Dr. Gerard Sanacora: There's clearly need for improved antidepressants at many levels. 1) Our current antidepressants, there's a substantial proportion, about a third of people that really don't obtain a great benefit. Even when they do obtain a benefit, it can often take six weeks or two months before they get a clinically meaningful change, and then there's still a relapse rate that hovers around 50% for people despite taking their medicine. There is great need for new antidepressants.

Whether ketamine is that type of medicine, I think it's a little too early to say. I feel very comfortable at this point for people that have failed multiple standard antidepressants, that this is something that we could offer under the right circumstances. At this point, I look at it and our clinical program looks at it as something very similar to ECT, especially not having that data that we need for long-term efficacy and safety. As that becomes more widely available, I think we could change where the risk-benefit ratio sits. But I think right now we're talking about this as a treatment for the more treatment-resistant patient, especially considering the fact that it looks like you are going to require ongoing treatments for the majority of people.

Dr. Perry Wilson: Do you worry about the potential for addiction here? This is a drug that has been abused, obviously.

Dr. Gerard Sanacora: We know it is a drug with some abuse liability, and we've seen it, especially in some parts of Asia and the U.K., it's become a fairly popular drug of abuse.

Dr. Perry Wilson: Toronto, Canada, I think has sort of an epicenter.

Dr. Gerard Sanacora: Toronto. There are a few places where this has become a significant drug of abuse, so I think there's no doubt that there's some risk associated with it. For the most part, where it's being given at most centers and especially at academic centers, it's being given under the supervision of a clinician, so it's not being given to take home, so it becomes a little bit harder to abuse in that sense. But there are real concerns. 1) For the individual, although there's been very few reports of individuals getting really hooked on the clinical treatment, but the potential is there, especially if we start opening up who is open to get the treatment. Then there's also the real concern for diversion. If this is a drug that can now be taken home, there's a real risk that it may end up in other people's hands who it really wasn't intended for.

Dr. Perry Wilson: Is that the primary reason why all these studies are using IV ketamine? Obviously, there's an oral formulation. It seems, if I were a patient, I'd just rather take a pill or is there a biological reason for that?

Dr. Gerard Sanacora: No, there's real issues with bioavailability. Orally it's very hard to predict the bioavailability and it's actually very low, so you would have to take quite a bit of the drug to obtain the plasma levels that we typically would get. That is a big part of it, and it's very unreliable. It's hard to predict what your plasma level is going to be with an oral dose. That is a big part of it. I think there is a secondary component that we really do want to keep tight control of how this is distributed.

Dr. Perry Wilson: Absolutely. What other areas besides depression might we see ketamine see some use aside from as an anesthetic, obviously?

Dr. Gerard Sanacora: It is very interesting. If ketamine is doing what we're seeing in the rodent models, if that's critical, it could have wide potential benefit. If we are seeing these changes in neuroplasticity and these changes in the way that the neurons are talking to each other and the way the circuits in the brain are actually talking to each other, this could have wide variability, obviously, for things like bipolar disorder, which there's already a few studies suggesting efficacy, possibly posttraumatic stress disorder. But spreading out beyond that, there's some real interest in whether this could be used in some of the neurologic disorders where increasing neuroplasticity could be beneficial, things like Parkinson's disease and others, even some preclinical studies, rodent studies have suggested in illnesses, developmental illness such as Rett syndrome, this may have a place. But these are all very early and much more work needs to be done before we can say it has true clinical utility.

Dr. Perry Wilson: I love to see an older drug sort of getting a new lease on life, and especially one with a history like ketamine. One of the nice things about these older drugs getting sort of new indications is that they're potentially inexpensive. Ketamine, I assume, must be off patent at this point. How much does it cost to get a ketamine treatment?

Dr. Gerard Sanacora: The cost is not in the drug when we're talking about standard racemic S-ketamine. The cost is really in delivery. The way it's being delivered at most academic centers and I think in most centers requires quite a bit of medical care and coverage, so really, that's where the primary costs are coming from.

Dr. Perry Wilson: A psychiatrist in their office is not going to be able to give ketamine infusions, right? This is a…

Dr. Gerard Sanacora: This is a real big issue and where do you draw that risk-benefit line. There clearly is some risk associated with the acute dosing of ketamine. There's changes in heart rate, cardiovascular demand is increased. For most of us, it's well tolerated, not a problem, but where do you draw that line and where it's safe? There's also the acute effects, as we said, in perception and cognition that can be pretty frightening to some people and requires some behavioral interventions at time.

In our mind, this is still a drug that requires some level of monitoring, cardiovascular monitoring, even respiratory monitoring, although, that's, I think, a much lesser concern at this point. This is a thing that can be done, I think, by a psychiatrist who is comfortably medically managing those type of things and has the equipment to monitor it. But I don't think this is something that's quite ready for use in the average clinic out there.

Dr. Perry Wilson: Dr. Sanacora, this is just an absolutely fascinating area of research. Congratulations on everything you're doing. We look forward to seeing the next set of results that come out and to find out whether ketamine is the next big thing in mood disorders. Thanks for joining me.