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If you're getting standard treatments, the chance that your depression is going to get better, it's around 10 % to 20%.
If you get ketamine, the chances you're gonna improve are like more like 50 % or maybe 75%.
Hey everyone, it's Rosie here.
Welcome back to Radioheadspace.
Depression is something I've definitely experienced, but never fully understood.
It's different for everyone.
It varies in severity and there are a myriad of treatments.
However, ketamine has come to the forefront of the conversation as a revolutionary treatment And it's because of a man named Dr. John Krystal.
Dr. Krystal is a pioneering psychiatrist and neuroscientist. And he was essential in proving that ketamine is an incredible treatment for depression.
Today, we're going to break it all down, how ketamine works in the brain, why it's offering hope to people who haven't found relief elsewhere and what the future of psychedelic assisted therapy might look like.
I'm so excited for you to hear this conversation.
Thank you so much for joining us, Dr. Crystal.
I wanna begin first by asking you what sparked your initial curiosity about the brain and mental health?
Was there a defining moment or experience that really ignited your passion in this field?
You know, it's interesting.
It goes all the way back to college.
In the summers after my first year of college and second year of college, I was working in methadone clinics, and in London in a clinic that actually prescribed both methadone and heroin to people who were opiate dependent.
And I think maybe one of the reasons I was interested in addiction was that my main interest in high school was music.
And I had a lot of musician friends, and I played in bands.
I had a number of friends who developed drug abuse problems, and so I thought that was an interesting problem.
Well, I came back to college, took a biochemistry course, and the teacher talked about how drugs essentially hijacked our body's internal opiate system to drive addiction.
And for some reason, that hit me like a ton of bricks that—wow, addiction has its basis in knowable problems. and if addiction which is so complicated has this kind of connection, then problems like depression and anxiety probably do as well.
And literally from that moment on, I was interested in this interplay between the most basic molecular aspects of brain function all the way up to the problems that people have in their lives.
And literally that's been my entire career working on that connection.
Yeah, thank you so much. And this actually brings me to the reason why I was so excited to talk with you, because in having this conversation about habits and addictions, one of my friends actually sent me an interview that you did that you were talking about ketamine and ketamine has been such a big topic right now.
I feel like I'm hearing it a lot these days.
so I'm curious for you, how did ketamine first land on your radar?
And if there was maybe something that just made you think, wow, this this could change everything in terms of mental health.
Sure. Well, you know, when you asked me, how did I get interested in ketamine?
All of a sudden, I feel very old.
And, and, and that's because I started thinking about testing around 1988, 1989, somewhere in there.
And the context was in those days, I was spending a lot of my time, we had created a schizophrenia research unit and what I did was, you might say, a little bit of a thought experiment.
And the thought experiment had to do with a change in the way I wanted to think about the biology of schizophrenia.
At that time, people thought of schizophrenia as a disorder, an illness of a particular chemical system in the brain called the dopamine system.
I didn't want to focus on dopamine, and so I thought, well, what I want to do is shift my focus.
And what I was really interested in was the higher brain centers, the cerebral cortex. And I thought, well, if it lived in the higher brain centers then it had a profound implication, because the cerebral cortex uses a very different chemical system to communicate.
And so I thought, well, what drug could I use to probe communication?
At that time, the drug that was most studied was a drug that I wasn't going to use, which was a drug called phencyclidine, or PCP, angel dust. So I thought, well, I can't really do that.
So what I'm going to do is give people a less potent and shorter acting version of phentcyclidine, which was at that point an anesthetic medication called Ketamine.
And what brought us to depression though was that the depression is in part a problem of communication in the brain.
I'm reminded of that great quote from Cool Hand Luke, you know, what we have here is a failure to communicate.
Right. And what's remarkable is that ketamine treatment and long -term treatment with other antidepressants to some extent as well, restores the capacity for more optimal communication among these various parts of the brain that are communicating in these circuits or modules of the brain that are involved in our emotion regulation and our problem solving and our resilience to changes in our behavioral flexibility and our capacity to experience pleasure and all of these things which get compromised when we're depressed.
We gave people who had been depressed for years, often, just a single dose of ketamine to see what it would do to their cognition and behavior, but what we saw was some improvement over about six hours, a little improvement, and some of the people reported feeling completely better by the next day.
I mean people who had been depressed for 10 years and we were shocked, I mean it's hard to describe how shocking it was to see people get better a day after a single dose of medication after being depressed for a decade or so because no treatment for depression worked like that.
And we'd never seen anything like that.
We did our study, we presented it for the first time in 1997, and I think mainly people thought it was funny.
I think they thought, well this can't possibly be that you give a dose of the medication and people get better so rapidly, even some people who had been ill for a long time.
So we had this initial study, then a group in at the National Institute of Mental Health replicated our study, our findings almost exactly and many other groups subsequently.
And that work over time, you know, led to ketamine being used as a treatment in the development of s -ketamine or Sbravado by Johnson & Johnson, which was approved by the FDA in 2019.
So, you know, we had presented the results in 1997, and it took until 2019 for it to get approved by the FDA.
But that also was a transformative moment because the drugs, all the other main classes of antidepressants, they were mostly discovered in the 50s.
How does ketamine work differently from the common antidepressants or the common SSRIs or Prozac or Zoloft?
How does it work? When you have an SSRI, you can think of it as boosting the serotonin system and you have to keep the serotonin system boosted as long as you're on the SSRI.
If you stop taking it, the effects can go away very rapidly.
What ketamine does by directly activating cortical networks and triggering these resilience mechanisms is produce changes in hours that take weeks to months to take place within SSRI.
So most of the benefit of ketamine happens after ketamine is already out of your body.
It's the brain's reaction to ketamine that's therapeutic.
And that's why in people who get treated long term they may only get a dose every several weeks in order to maintain the clinical improvement produced by ketamine.
As you can see, these are kind of fundamentally different kinds of treatments.
Yeah, do you think that we're at the beginning of a new era in mental health treatments, where fast acting solutions like ketamine will be more commonly used throughout?
You know, mental health treatments, etc. Yeah.
You know, this is the most exciting time in the entire history of the field of psychiatry.
And I just think that the understanding that we have of neuroscience and brain function and the tools that we have to study brain function are so much greater than before.
I think one of the things that ketamine did in terms of the practice of psychiatry was to open the door to treatments that had more profound effects on cognition and behavior.
Until that time, we did prescribe drugs that had powerful behavioral effects, but nothing like what we have with ketamine and then psychedelic drugs and MDMA.
And these are drugs that have much more powerful effects on consciousness, have the possibility of producing rapid clinical improvements, and may work for patients that haven't responded to the older treatments.
What have been the biggest issues in resistance with ketamine that, in your experience, or that you've heard arguments or people that, you know, are sort of really resistant to these studies and this information?
The resistance to ketamine, I'd say is more ideological and is a challenge that we're going to face for a while going forward, and is related in part to the abuse liability of ketamine.
There are some things about ketamine that make it challenging as a take home drug and that need to be addressed if people are going to be treated safely with it.
First, ketamine is only effective in a very narrow dose range.
The typical dose is a half a milligram per kilogram, and it's administered intravenously over forty minutes.
That's the window where ketamine is shown to be antidepressant.
If you double that dose, you start to get into the range where some people will start to look like they're anesthetized.
And when you're in the anesthetic range, there are several studies that show that ketamine is not antidepressant.
So you can under -dose ketamine, in which case you feel a little woozy, but you don't get any antidepressant effect.
And you can overdose ketamine, in which case you're anesthetized and you don't get any antidepressant effect.
And so the dosing of ketamine has to be very carefully managed, if we want people to get antidepressant benefit from it.
Is the treatment of ketamine meant to sort of be a short term treatment, eventually people getting off of it and sort of establishing their own homeostasis from that point on?
Or is it meant to be a long -term treatment like you're taking a medication for the rest of your life?
You know, what we've seen, and I think what I hear as I talk to people who are running clinics is, there's a group of people who are inadequately responding to whatever their current treatment situation is, and have needed ketamine to kind of kick -start their recovery, And those people often, you know, will get somewhere between, you know, six and twelve sessions or something like that.
And that's all they'll get, and then they're done.
And their life is back in gear, and their treatments work, and they don't seem to need it.
Others, particularly with those who have the most antidepressant -resistant symptoms and the most chronic, long -lasting course of depression, those people often need booster sessions.
whether every two weeks, once a month, whatever, on a long -term basis.
And for those people, ketamine can be really helpful.
There's some really exciting data about people who had been treated on average for 42 months with S -ketamine, so almost four years.
And they found that over that long period of time that there was about a ten -fold reduction in suicide attempts in the group that was treated with esketamine compared to the comparator population.
There was about a five -fold reduction in death by suicide and it's really important when we talk about depression that depression is potentially a lethal disease and one of the ways that risk is obviously expressed is through suicide.
But there was also a three -fold reduction in all -cause mortality, which is the chances of dying of heart disease, of stroke, of other medical illness also goes down when your depression is more effectively treated.
How are people getting?
Well, I mean, I know of a couple people who have acquired ketamine and I wouldn't say from a ketamine clinic.
I live in LA, and I know that there are really great ketamine clinics here, or from what I've heard. I'm curious, how would somebody who wants to inquire about ketamine treatments approach the search for how to acquire it or how to get it prescribed?
Well, I think that in the best circumstances people are often in treatment of one kind or another already with a treater who's looking out for their best interests and thinking about what their treatment options are and who will stick with them through their experience with ketamine and afterwards.
And so that ketamine is a procedure but it's not necessarily the whole treatment.
And so I think that perspective is very helpful because there's a lot about recovering from chronic depression that benefits from support.
You know, if you've been depressed for ten years, say, five years, everyone around you has begun to think of you as a person who's depressed.
And when your world is built around you in this way, and then 24 hours after a single dose of ketamine, you feel like going out to dinner.
You want to watch a movie.
You don't like the way the furniture is arranged.
That can cause real problems in a relationship, right?
And so, people often need to support and therapy to manage the fact that they are doing better and in so doing have destabilized their life.
And that's one of the reasons that I think about ketamine as an intervention and the treatment, the bigger picture.
yeah oh I love that I'm curious dr. crystal for you what are you most excited about right now with the research and everything that we discussed with regard to ketamine what are you looking forward to the most and what excites you the most currently I think that you know the overall the main thing is that just what a transformative impact ketamine is for people with depression.
When I say people, I mean everybody, all people who struggle with depression, whether they're struggling with it on the side of suffering from depression themselves, or being a family member of somebody with depression, or being somebody who's treating people with depression and having the experience of really struggling around recovery, and the idea that could now have a fundamentally new option, that substantially, meaningfully increases the likelihood of a really significant benefit, to me is just a really profound idea.
I've heard it said that depression is the single most contributor to functional disability worldwide.
As I said earlier, it is such an exciting time, to be on my end of it, of kind of trying to figure out the biology of depressions and come up with new treatments and, but really, it's a really different, it's a really different context for having depression and getting treatments.
Yeah, thank you so much, Dr. Crystal.
It's been such an enlightening conversation.
I've learned so much and I continue to be fascinated by how magnificent and complicated the computer of the brain is, right?
I'm just I'm so, so, so intrigued and excited to learn about how the brain functions and and it's always really interesting to hear about cutting edge treatments that are available especially when we have so many people that are struggling with depression and anxiety and addiction so thank you so much for this very educational and enlightening conversation.
For the people that are listening to this where can they go for more information or if they want to learn more about you.
So if they want to learn more about me they can go to the website for the Yale Department of Psychiatry and if they want to get more information about mental illness, the website of the National Institute of Mental Health is really got a lot of good information about depression, the website for the National Center for PTSD, ncptsd .va .gov, or that's the email address, the NCPTSD website, National Center for PTSD website's got wonderful information about PTSD for family members, for people struggling with PTSD, for clinicians.
The National Institute on Alcohol and Alcoholism, Alcohol Abuse and Alcoholism, NIAAA, has wonderful information about alcohol use disorder, National Institute on Drug Abuse, similarly information about substance use disorders and addiction.
So there are a lot of resources out there, and there are just so many opportunities to find help and to find a path to getting better.
Thank you so much, Dr. Crystal, for your time and for this conversation.
My pleasure. Thanks so much. Hey, friend, I know how this feels.
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