- Welcome to Healthy Minds.

I'm Dr. Jeff Borenstein.

Everyone is touched by psychiatric conditions, either themselves or a loved one.

Do not suffer in silence.

With help, there is hope.

Today on "Healthy Minds."

Today I continue my conversation with leading expert Dr. John Krystal about potential new medications for psychiatric conditions.

That's today on "Healthy Minds."

(gentle music) This program is brought to you in part by the American Psychiatric Association Foundation, the John & Polly Sparks Foundation, and the Woodnext Foundation.

(gentle music) John, I'm gonna shift gears again and speak about another new medicine that's been developed to treat psychosis, to treat schizophrenia.

And I'd like you to share with us how that medicine is different than some of the traditional medicines for those conditions.

- Well, this is another story that's near and dear to my heart.

As at various, over my career, I've also tried to search for a drug that would be the first meaningful alternative to blocking dopamine D2 receptors on the, in service of treating psychosis symptoms in schizophrenia.

So in, I think it was 1951, a drug called Chlorpromazine was identified.

In North America, it was first administered to people with schizophrenia in 1954.

And since that time until this new medication known as KarXT or Cobenfy, all drugs that treated symptoms of psychosis associated with schizophrenia worked essentially through the same mechanism, which is blocking the dopamine D2 receptor.

And the reason that these medications are therapeutic is that there's one part of the brain where there's too much dopamine release.

And when you give a dopamine D2 receptor blocker, you normalize the level of stimulation of those dopamine D2 receptors.

However, dopamine is released all throughout the brain.

And so when you block dopamine D2 receptors outside of that little region where you have dopamine hyperactivity, you create dopamine deficits.

And those dopamine deficits can cause side effects that look like symptoms of Parkinson's disease, even though you don't have the illness of Parkinson's disease, but you have functionally a deficit in dopamine signaling in the brain that can cause tremor, restlessness, muscle spasms, involuntary facial movements.

It can make people feel dulled or not quite fully engaged with what's going around them.

And these dopamine deficits probably impede the overall beneficial impact that dopamine D2 receptor blocking drugs have.

In other words, they're very helpful for many people with schizophrenia or other psychotic disorders to reduce dopamine, reduce symptoms like hallucinations, like hearing voices or delusions in inappropriate beliefs.

Now so we've been looking for decades for a drug that could treat these symptoms without blocking dopamine D2 receptors.

- Because, and I just wanna interrupt for a second, because you make an important point that while the current medications, the traditional medications are effective for some of the key symptoms, they don't treat certain symptoms that we'll get to in a little bit.

And some people experience the medications even if they help with the symptoms as worse than the illness itself because of some of these side effects.

So coming up with a new approach can make all the difference in the world for many people.

- That's right, and you can imagine that if there's a balance of risk and benefit that is not favorable, that people stop taking the medication.

And when they stop taking the medication and get a worsening of their disorder, they get into this negative kind of cycle in their lives where they're in the hospital taking medications.

They take it for a while when they're out of the hospital, but then they stop taking the medication.

The symptoms come back, they're back in the hospital.

And you know what we all want, people who have the illness, their families, their treaters, the society, what we want for these folks is to have stability in their lives so they can get jobs, have productive daily activities, build their social relationships in positive ways and achieve the kind of recoveries that they want.

But we haven't had the kind of alternative treatments that we've needed.

Now, many years ago, 2008, a colleague of ours led a study in which he tested the core therapeutic piece of Cobenfy, which is a drug called xanomeline.

And he studied it in patients with schizophrenia and showed that it was an effective medication for treating psychosis and had some other benefits even though it didn't block dopamine receptors.

However, xanomeline was not tolerable.

It produced GI side effects, excessive salivation, a variety of cardiovascular side effects.

It affected your heart and blood pressure and things like that.

And so it was kind of put on the shelf.

What a company called Karuna Therapeutics led by Dr. Steve Paul and others did was to combine xanomeline, this drug that had been sitting on the shelf with a drug called trospium.

And trospium blocked the expression of some of the side effects of xanomeline.

So xanomeline plus the peripheral blocker trospium was a much more tolerable drug that preserved the effectiveness of xanomeline.

And that combination is called KarXT or Cobenfy.

And that's the medication that was approved.

So here we had, with the approval of Cobenfy, the first drug to treat symptoms of psychosis without blocking the dopamine D2 receptor.

And the implication of that is that some of the side effects that we associate with the treatment of psychosis with the standard medications, you really don't get those side effects in the same way with Cobenfy.

You really don't get the extra extrapyramidal motor side effects, the tremors, the other side effects that I mentioned earlier.

And you don't get that dulled feeling in the same way that you do with some of the dopamine D2 receptor blocking, anti-psychotics.

- Potentially a major advance in treating these conditions.

And in addition to that, I'd like you to speak about what we refer to as the negative symptoms of schizophrenia and potentially the effects of this medication on those symptoms.

- Just as we were talking about with depression where there's been a lot of public attention on some aspects of the illness, but not so much attention to the other aspects of the illness, we have the same kind of situation with symptoms of schizophrenia.

So there's a lot of public attention on psychosis because it's a very prominent feature of the illness, you know, the hallucinations and the delusions, and to some extent the disorganization of thought and behavior.

And these were the targets of the dopamine D2 receptor antipsychotics, and they did that job reasonably well.

But it turns out that schizophrenia has other dimensions that are not so well served by these dopamine D2 receptor blocking treatments.

One cluster of symptoms are sometimes called negative symptoms because these are experiences that we all take for granted that are sometimes blunted in people who have schizophrenia.

So the capacity to experience pleasure, to be motivated, and to look forward to the future, to the kind of, the capacity to easily express the full range of emotions, these symptoms which are sometimes very prominent in people really get in the way of their lives because if you lack motivation and engagement, you tend to become very socially isolated.

You tend not to do productive activity during your day.

And all of that isolation feeds forward and contributes to overall poor outcomes in schizophrenia.

Now there are, you might say, cousins of negative symptoms, the cognitive impairments associated with schizophrenia, which along with the negative symptoms often compromise people to live up to their potential and achieve in their lives, either in their jobs or other kinds of activities, what they hope to achieve.

Now the original study conducted by Dr. Shekhar and his colleagues many years ago reported some promising results with Cobenfy improving cognitive function in people with schizophrenia.

While the published data so far have not yet identified an overall significant beneficial effect of Cobenfy on cognition, some secondary analysis suggest that this domain, the cognitive impairments of schizophrenia warrant further study as a potential area of benefit that Cobenfy may provide.

- So hopefully for people who may not fully benefit from the current medications for schizophrenia and other psychotic disorders, this new approach will make a big difference in their lives and potentially other additional new medications that may grow from our experience with this.

I want to again shift gears.

We've been speaking about medications that are available at this point, but now there's a lot of work going on on other medications that are not yet ready for prime time, and one that's received a lot, one area that's received a lot of attention are the psychedelics.

And I'd like you to speak about the psychedelics, where we are and where we may be going in terms of them as useful treatments.

- The psychedelic drugs are really different drugs from ketamine, even though ketamine, even though ketamine produces perceptual alterations, it does not produce the full blown hallucination states that psychedelic drugs do.

In other words, if you were in a room and you took a psychedelic drug like psilocybin, you might see a whole kind of movie unfolding around you of objects and things that aren't there in the room appearing to you in ways that are quite different.

And whereas ketamine is much more likely to distort what you're experiencing in the room, the psychedelic drugs are much more likely to create an experience of kind of wonder and awe.

Psychedelic drugs work via a very different initial target than the ketamine does.

Psychedelic drugs stimulate a receptor called the serotonin 2A receptor, and ketamine blocks a receptor called the NMDA glutamate receptor.

So they're affecting different, very different initial targets.

Psychedelic drugs when given, activate cortical networks and create hallucinations, we believe, by competing with your sensory experience for consciousness.

In other words, when you give, take a dose of ketamine, it's distorting your sensory experience, but not creating an alternative experiential narrative so much.

Psychedelic drugs, much more are creating this different experiential narrative that is competing with what you're experiencing in your normal sensory world for control of your consciousness.

So these drugs like ketamine though, have some common downstream impact on brain circuits.

Just like ketamine, psychedelic drugs have the potential to restore brain structure and normalize brain function associated with depression.

However, there's something that happens with psychedelic drugs that happens more commonly than it does with ketamine, although people have told me that it has happened with them during their ketamine treatment.

And that is that there's something that people who get the psychedelic drugs often experience during the administration of that psychedelic drug, which feels extremely important and relevant to them.

Sometimes, there's a drug called 5-Methoxy DMT, which is a different, one of the group of psychedelic drugs, you might say a cousin of psilocybin, which is the drug that's been studied initially.

But this drug is a powerful psychoactive psychedelic drug.

And people experience often cognitive whiteout when they take the drug.

So they can't even tell you what it was that they experienced in any kind of clear way.

And yet they still often say that this was an extremely important experience for them.

So it's possible that either the subjective experience itself is perceived as meaningful or that the drug triggers an activation of the circuits in the brain that underline a feeling of importance, salience, meaningfulness, something like that.

So that people sometimes come out of these treatment sessions with a drug like psilocybin feeling that something important and valuable has happened above and beyond the alleviation of their depression symptoms.

Psychedelic drugs in some ways are more powerful cognitive experiences than what you typically get with ketamine, which itself is a pretty powerful experience, and it's so powerful that some people need to be prepared for it very carefully about the kinds of experiences that they're likely to have and how to manage those experiences.

Also, that people need to have a coach there throughout the session to make sure that they're managing the experience constructively, and they need a number of debriefing sessions after their exposure to the drug to help them make sense of the experience that they had.

Some people who take a drug like psilocybin will experience recurrence of their traumatic experiences or experiences that are very shameful or troubling to them.

They can feel overwhelmed and even suicidal.

So this drug which is given to alleviate symptoms like suicidal thoughts and feelings may itself trigger those thoughts and impulses.

And that's why the psychotherapy framework around these psychedelic treatments is so extremely important.

Because these experiences are so powerful, psychedelic treatments are probably not for everybody.

- When thinking about the psychedelics, how can we minimize, take away the risks associated with the hallucinations that occur with the psychedelics?

- You know, this is really an important and timely question because there are a number of groups around the world that are trying to figure out whether it's possible to preserve, to engineer out the risk for hallucinations when a psychedelic drug is administered.

You know, the original way that people thought that we might be able to do that is by micro dosing, giving a very low dose of a psychedelic.

But micro dosing strategies have yet to be shown to be effective for the treatment of depression.

Another strategy is to design new kinds of molecules that stimulate the target, brain target for psychedelic drugs, the serotonin 2A receptors, but when they activate the drug, they don't produce the full effect of stimulating the receptor, only part of that effect.

These drugs are called biased agonists because they only produce part of the effect of stimulating the serotonin 2A receptors.

And there are several companies that are trying to design these highly biased agonists with the hope that they will produce the therapeutic effects associated with psychedelics without the hallucinations and the associated risk.

Another strategy is to combine medications.

And this is a strategy that my colleagues and I have been studying at Yale, which is to take a psychedelic drug which normally produces hallucinations and to give another drug that blocks the cellular mechanisms through which the hallucinations, but not the therapeutic effects of the psychedelic drugs are expressed.

And we think that these combination treatments may prove to be a way that a lot of the benefit associated with psychedelic drug treatment can be produced while minimizing the risks of hallucinations and other negative effects of psychedelic drugs.

- One of the areas that research has focused on is post-traumatic stress and the use of psychedelics.

I'd like you to say a little bit about that.

- So I'm gonna draw a distinction that's not always drawn.

I mean, it's usually drawn by neuroscience types, which is that MDMA is a drug which is sometimes grouped with the psychedelic drugs, but is actually a very different kind of drug.

You can think of MDMA as a cousin of the medications that are prescribed for the treatment of attention deficit disorder.

These are a family of medications called amphetamines, and amphetamines are often given to people with attention deficit disorder or sometimes for certain kinds of depression.

Now, but MDMA is not hallucinatory, so it is not really a full psychedelic drug, but it does, has produced in studies very promising changes for symptoms of PTSD.

There were some limitations of the studies that were conducted that prevented the FDA review panel from approving the MDMA at that time, but there's no doubt that the signal, the therapeutic signal from those MDMA studies are very encouraging, consistent with the reports that people have shared publicly about their experiences of MDMA treatment for PTSD.

I think that the decision to not approve MDMA was consistent with some of the limitations of the studies that were conducted, but I hope that MDMA will continue to be studied because it seems like a very potentially promising future approach for the treatment of PTSD.

- I'm gonna shift gears again and speak about a medicine that is also new, not used directly for psychiatric purposes.

It's become very popular for weight loss, and that's the GLP-1 medications.

And I'd like you to speak about why those medications potentially may be effective for some psychiatric conditions.

- These days, the main question is what don't GLP-1 agonists treat?

GLP-1 is a peptide released by the gut that affects a variety of functions, including the feeling of satiety, and as a result, it can help people who have difficulty controlling their appetite to reduce their food consumption.

So that action itself may lead to this class of drugs having a role in psychiatry because some of the medications that we prescribe produce weight gain, and some of the disorders that people struggle with like schizophrenia actually have built into the disorder some resistance to the hormone insulin, which regulates, has a variety of metabolic functions.

So it may be that GLP-1 agonists like semaglutide play, can play a role in weight gain associated with these psychiatric disorders or their medication treatments.

There's a new area that has opened up with GLP-1 agonists that has to do with their ability to control appetite, but in this case it's not the appetite for food, but the appetite for alcohol or other abused substances.

And there's some intriguing clinical data that suggests that this family of drugs may be useful for reducing alcohol consumption, reducing smoking, potentially reducing stimulant use.

These studies are not, you know, this is still early days in this line of work, but there's a lot of interest in these medications.

- John, I wanna thank you for sharing all this information, so much detail, but in a way that is user-friendly for the lay public.

And I wanna thank you for the work that you've done that have had such an impact on our understanding of the brain and illness and treatment of these conditions.

Thank you so much, - Jeff, this has been a real pleasure, and thanks for having me on today.

(soothing music) - [Jeff] Do not suffer in silence.

With help, there is hope.

This program is brought to you in part by the American Psychiatric Association Foundation, the John & Polly Sparks Foundation and the Woodnext Foundation.

(soothing music)