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Roughly one in 10 Americans takes an antidepressant to aid in the debilitating symptoms of clinical depression, but for some medications don’t work. In this episode, Amit Anand, MD, discusses the evolving therapies for treatment-resistant depression, including ketamine and esketamine.

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Ketamine Research for Treatment-Resistant Depression (Early Work Through Current State)

Podcast Transcript

Intro:  Neuro Pathways, a Cleveland clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab and psychiatry.

Glen Stevens, DO, PhD:  In the US, it's estimated that 16 million people are living with depression and approximately one third of depressed patients are considered treatment resistant. Ketamine was once used mainly as a surgical anesthetic in operating rooms and is now gaining ground as a promising treatment for depression. In today's episode of Neuro Pathways, we're discussing ketamine research for treatment resistant depression. I'm your host Glen Stevens, a neurologist neuro oncologist in Cleveland Clinic's Neurological Institute. And today I'm pleased to be joined by Dr. Amit Anand. Amit is vice chair for research in Cleveland Clinic's Center for Behavioral Health and director of the Mood and Emotional Disorders Across the Lifespan Program at the Cleveland Clinic. Amit, welcome to Neuro Pathways.

Amit Anand, MD:  Thank you. Thank you for having me.

Glen Stevens, DO, PhD:  And I would just say at the start, that during the pandemic and all the social isolation, I think that this becomes an even more important topic to bring up and is affecting many individuals across our nation. Perhaps with the first question, when we look at patients coping with depression, we most often find relief in antidepressants, but for those experiencing treatment resistant depression, standard medications provide little to no relief. Can you start our conversation by defining treatment resistant depression?

Amit Anand, MD:  Treatment resistant depression I think it's, as you said, it is when you say treatment resistant, is it is resistant to antidepressant, the commonly use antidepressants, oral antidepressants such as pro fluoxetine or Prozac or the SSRIs or some of the dual reuptake inhibitors. All the antidepressants that we have had for the past 30, 40 years or more, if a person does not respond to that. It is not that the depression will always be treatment resistant, but it is resistant to the commonly used antidepressants.

And there are many definitions of treatment resistant depression, but the most commonly that we used are like if a person does not respond to at least two adequate trials of adequate mean adequate dosage, which is the full doses that is recommended, as well as duration because many of these antidepressants take anywhere from six to 12 weeks to actually start acting. If somebody is only taken it for a couple of weeks, that doesn't count. An adequate trial of at least two antidepressants of preferably of different class that we would call probably it will be the most literal definition of treatment resistant depression. Now, some people want three, three different antidepressants of three different classes and so that would be a more conservative definition of treatment resistant depression.

Glen Stevens, DO, PhD:  I know you have been in the field for many years. Can you take us through the evolution of therapy for patients with treatment resistant depression and how it's changed over time?

Amit Anand, MD:  Yeah, that's a very interesting topic and almost it's like a history of psychopharmacology. But initially, in the 1950s or 60s, the main antidepressants, which originally came out was imipramine, which is a tricyclic antidepressant and it affects various neurotransmitters. And then the monoamine oxidase inhibitors were also available at that time. Things like phenelzine which is a monoamine oxidase inhibitor. And they were the first antidepressants to be discovered and used and they still in some respects remain the most effective medications until now.

However, they had a lot of side effects. For example, the tricyclics, you would have dry mouth, a lot of anticholinergic side effects, constipation, blurring of vision. And then if taken overdoses, they could be fatal. There was a lot of sort of dissatisfaction with that. And of course the monoamine oxidase inhibitors, you can get malignant hypertension if you eat the wrong things.

In the next big evolution in antidepressant was when Prozac or fluoxetine was discovered or the SSRIs were discovered in the early 1990s. And the SSRIs were much better tolerated. There are less side effects and they were found to be more or less equally effective for depression. That was one big thing. And for a long time, since the 1990s to even now, they are the most widely used antidepressants. Then there were a few sort of changes to that, that people want to make like dual reuptake inhibitors, which will act both on norepinephrine and serotonin. Something like Venlafaxine or Effexor came up or duloxetine or Cymbalta came up and then another medication called Wellbutrin, which is quite different or bupropion, which acts on the dopamine reuptake. But all of them are based on what is called the catecholamine hypothesis. That the idea that if you increase the catecholamines in the brain, your depression will improve.

And that's what we've been through for the last two, three decades. That's what has been the main mode of treatment. However, more and more studies were coming out that even these antidepressants are only helping, say at the most, half or two thirds of patients to get response or remission. People are looking at different things. Lately, this last year was the first time that a new antidepressant was actually approved by the FDA called as intranasal ketamine, or a Spravato, which can be taken intranasally. However, ketamine as such, as a possible antidepressant was discovered in the late 1990s and the first paper, I was part of that first paper, which came out in 2000 from Yale when we, the first study of ketamine as an antidepressant was discovered.

Glen Stevens, DO, PhD:  And any comments about ECT and its role?

Amit Anand, MD:  The only nonpharmacological treatment, and ECT is even older than antidepressants. Has been around with us for about 70, 80 years now. And so when people did not respond to antidepressant, had severe depression or they were in imminent risk of harm, then ECT. That's a whole class of different treatment for depression, which are called stimulation treatments. ECT was the first one, then magnetic stimulation with transcranial magnetic stimulation came up and then vagus nerve stimulation came up and then deep brain stimulation came up.

Now I should say that, one thing about psychiatry treatments is that they usually have been available for other indications, many, mostly neurological indication and they're adopted in psychiatry when people feel that well, this thing is also probably helping mood. ECT, was used for several other things, for seizure therapy and other things, same thing with TMS, for VNS and for deep brain stimulation, which was used for Parkinson's disease. It is not that at any time, any indication that they were more effective than medications, but they were available. And then when people did not find that the treatment with antidepressant was helping, then they would give these treatments. ECT, I would say, has had some indication that it may be more effective in treating patients who did not respond to antidepressants.

Glen Stevens, DO, PhD:  It's quite exciting to get to talk with you since you've been around with the ketamine experience. And I'm just curious, was it serendipity that it was found that patients who received that anesthetic, their depression did better for a period of time? Or do you have a story for it? Or how did they get onto it?

Amit Anand, MD:  Yeah, definitely I have a story. fortunately or unfortunately, it was also found through serendipity or chance. At Yale, ketamine, it's a derivative of phencyclidine or PCP which was also thought to be anesthetic agent initially, but it causes psychosis. They formed a milder version of it which was ketamine, but ketamine also causes psychedelic experiences or psychosis. At Yale, the person who was actually studying it, actually in healthy subjects, he was trying to make a model of psychosis or schizophrenia by giving intravenous ketamine. And then he was trying out to people who are, and now I should also say that this is the use in psychiatry from that point is for sub-anesthetic doses of ketamine. It's not as high to put somebody to sleep. It is actually a sub-anesthetic dose anywhere from 0.5 milligram per kilogram now over 30 to 40 minutes.

Just to give it as an infusion and people would have all these, what would be called sort of psychedelic experiences. And it was being used as a model for schizophrenia. And then the person there was trying to actually use other medications to decrease the psychosis and use it as a model for developing treatments for schizophrenia. However I was actually in the mood disorders group, they're different people that other person was in the schizophrenia research group. And there was at that time also, some indication that NMDA antagonists may have some antidepressant properties. Things like amantadine were around at that time. There was some evidence that they have some euphoric effects. Somebody said, "Well everyone, let's try out ketamine in depressed patients." And maybe originally, people were skeptical. We had a little bit of hard time getting it through the IRB, but we finally got it.
And there was a colleague of mine, Angela Cappiello who actually is an Italian psychiatrist who had just come to the US and she did the first study. And it was pretty amazing. And I still remember, she came to our group and said, "It's pretty amazing. I gave this ketamine to this depressed person, it's been three days and he's saying he's not depressed at all." That was pretty amazing and we started a small study about eight to 10 patients. There are a lot of other medications like amphetamines, which can cause euphoria and other things but with ketamine you give one dose and then at least for seven days, you can have the persons who respond say, "Well, I don't have any depression anymore." It was pretty amazing.

And the idea at that time was that, as I said, the usual antidepressants take four to six weeks or more to act. And the idea was, can we find something that works fast just like ECT? We thought we had found something which can work very fast. However, as I said, the duration of a single infusion was for about seven days. And after seven days, the person relapsed back into depression. It was still a short period of elevation of depression, but more than the imaginary effect of say a stimulant like amphetamine or something like that, but not as much as for antidepressant, which was if taken for a longer term would actually for many months or years have an antidepressant effect.

Glen Stevens, DO, PhD:  If we move forward to esketamine, why don't you tell me a little bit about its use and how you've used it, or how you're using it, or what population you would use it in?

Amit Anand, MD:  Esketamine is very recent. Many people would not have much experience with it at this time. And it is intranasal as ketamine. Ketamine has been around, as you said for a long time. The older forms of ketamine available, intranasal forms are available, then the two isomers and anomers of ketamine esketamine and arketamine. And so both of them have been available for some time. People have been using it for a long time. I think the intranasal ketamine because people were not using it that much, I think the pharma company was able to get a patent on that and make an intranasal formulation of that and then start doing trials in the last few years. Though, there's a large, since our original study in 96 or so and the paper was published in 2000, for nearly 15, 20 years, there have been lots and lots of studies done on intravenous ketamine as an antidepressant.

And it is pretty clear that at least one infusion of ketamine can cause antidepressant effect, but to sustain it, it is not very clear what you have to do, whether you have to keep on giving IV ketamine or to something else. As ketamine has been around recently, and they're supposed to have possibly a similar effect as intravenous ketamine. And as you would realize, it's much easier to give than intravenous ketamine. However, it is about one dose, I think costs about $800 or so while IV ketamine, one dose is $4. There's a very big premium price on it, but because the FDA has now approved it, it will be covered by insurance companies to do that.

Glen Stevens, DO, PhD:  Currently you hold a multi-year P. Corey grant with the Cleveland Clinic. Can you provide insights as to what research you and your team are currently conducting?

Amit Anand, MD:  Yeah. Now ECT as we discussed is one of the most time tested treatment for resistant depression. In fact, psychiatry in some ways, synonymous with ECT. Somebody's seen the One Flew Over the Cuckoo's Nest or some of those movies. However, ECT has a very bad reputation because as it is depicted in movies and literature, that's one thing. It does cause memory problems. And also, you have to go under general anesthesia to get ECT. It's a bit difficult treatment to give. I would say generally patients don't like it, going through ECT. Doctors however are willing to prescribe it because it has been found to be very effective. And it has only survived for 78 years because we didn't have any alternative. Now that ketamine is available, we have an alternate for treatment resistant depression, something that works very similar to ECT. Works very fast, even decreases suicidal ideation.

The idea for the study that we are currently doing, a very big study is to actually directly compare ECT and ketamine. We are taking people who are referred for a ECT and we approached them and say, "Well, you want take part in this study?" And if they say yes, then there's a 50/50 chance of them getting ECT treatment or ketamine treatment. And we are looking at whether there will be any difference in the response after three weeks of treatment with either ECT or ketamine. This is a real life, real world study in which there's no placebo or we take it. Anybody for whom ECT is clinically indicated we are taking them in and there's a lot of clinician discretion in choosing the treatment and how to give it. It'll be just like real life. The question we are trying to answer is, if somebody is coming from people who come for ECT, instead of ECT, if they got ketamine, will they get equally better?

And even they get a little bit less equally better, whether it is worthwhile because ketamine does not cause memory problems, does not require anesthesia and actually most of the time it is a pleasant experience getting the ketamine intravenously. And there are side effects of ketamine like hypertension and it is a drug of abuse though there's not been much evidence that use of it for depression has caused abuse, but there are issues like that. We have to keep that in mind. But it will be a dramatically different experience to getting ECT, getting ketamine treatment. We are doing that study. It's probably the largest study ever done for ECT and certainly for ketamine. We have to do 400 subjects in the next and we have only done about three years of this and we have completed about 270 subjects have gone through the study. Besides Cleveland clinic, there are sites at Yale, Hopkins, Baylor and Mount Sinai.

In terms of additional studies, one other major part of depression, consequence of depression is people sometimes harm themselves or commit suicide. And the great thing about ketamine is that is it also shown to have anti-suicidal effects. Again, the only treatment available for quick treatment for somebody who has depression and maybe has some suicidal thoughts was ECT before, but now ketamine has also been added and Spravato or intranasal esketamine has got approval from the FDA for that use. They didn't actually show a difference in a change in suicidal ideas with esketamine compared to placebo, but they did see that our depression decreased much more with esketamine than placebo. It could also be used for that purpose. And we will also be doing research in that respect later on.

Glen Stevens, DO, PhD:  Dr. Anand, would like to thank you for joining us today. We're interested to see how your work continues to change the way we manage depression and looking forward to better treatments for this refractory patient population. Thank you very much.

Amit Anand, MD:  Thank you very much for having me.

Outro: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our consult QD website. That's or follow us on Twitter @CleClinicMD, all one word and thank you for listening.

Neuro Pathways

Neuro Pathways

A Cleveland Clinic podcast for medical professionals exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neurorehab and psychiatry. Learn how the landscape for treating conditions of the brain, spine and nervous system is changing from experts in Cleveland Clinic's Neurological Institute.

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