- 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.

(dramatic music) Today, on "Healthy Minds," what new medications may be available and what new medications may be right down the road to help people with psychiatric conditions?

Today, I speak with leading expert Dr. John Krystal about new medications that have become available and other medications that perhaps soon will be available to help those who are not yet benefiting from the current treatments.

That's today on "Healthy Minds."

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

(dramatic music) John, thank you for joining us today.

- Jeff, it's my pleasure.

- I wanna jump right in and talk about some of the newer medications that have become available to us over the last few years.

And I wanna start with one that you've had a crucial role in its development, and that's ketamine and esketamine.

Tell us about where we are, what we know about the use of those medications.

- Sure.

You know, we've had antidepressants since the early '60's and we have a lot of different kinds of antidepressants and they help a lot of people, but there is still been an efficacy gap that large numbers of people treated with the standard antidepressants, often in combinations with other medications, still find that their depression doesn't improve, and that their lives, the quality of their lives are compromised.

Their ability to function at home and in the workplace suffers.

And so ketamine and esketamine represent a fundamentally different kind of antidepressant relative to these standard medications.

And they work through a different chemical system in the brain.

The standard antidepressants work through what are called the monoamine systems of the brain.

These are chemical systems in the brain that have names like dopamine, serotonin, and norepinephrine.

And ketamine and esketamine target a different chemical system in the brain called the glutamate system.

It happens that glutamate is the main information highway for the higher centers of the brain, like the cerebral cortex and the limbic system.

In other words, the parts of the brain that control thought and emotion.

And so way back in the 1990s, my colleagues and I gave single doses of ketamine to patients with depression and found a remarkable thing, which is that unlike the standard antidepressants where people have to take the medications for several months in order to get the full benefit of the medication, we found that some people could start improving within hours of a dose of ketamine and feel like they were fully back to themselves within 24 hours.

So the rapidity of the onset of the benefits from ketamine and esketamine, esketamine is sometimes known as Spravato, that the rapidity of the benefits of these medications was striking and unlike anything we had seen before.

- I just have to interject here because when you and I went to medical school, and it was at about the same time that we were each in medical school, the thought of an antidepressant working so quickly, it wasn't even on the table.

We didn't even think of it in that way.

- Yeah, you know, we couldn't imagine it.

And in fact, when we saw it happening right in front of us, the first question we had was, "Is this real?

Are people really getting better so rapidly?"

And it was really important to have other research to really strongly make the case that it's very common for people to get rapid responses to ketamine or esketamine.

And that those responses can be maintained by periodic doses of the medication given once or twice a week to start and then less frequently in longer term treatment.

But ketamine and esketamine have certain other benefits that are often not appreciated.

The first is that these medications are extremely effective for those depression symptoms that haven't responded to other treatments.

So people are often in psychotherapy and they get different medications sometimes in combination, as I was saying before, and they think there's no hope.

There's no possibility of they're getting better.

They've already tried treatment and it doesn't work.

Well, ketamine and esketamine seem to be distinctively effective for that group of symptoms, for that group of patients.

And that's really remarkable.

In fact, some of the recent studies suggest that ketamine is more effective than any other FDA-approved medication for those treatment-resistant symptoms.

And that ketamine and esketamine are as effective as electroconvulsive therapy, even though electroconvulsive therapy, ECT, sometimes has a nickname of shock treatment that is a little bit scary and misrepresents the treatment's really like, but ketamine seems to be as effective for these treatment-resistant symptoms as electroconvulsive therapy.

In long-term studies of people who are treated for four years, about four years on average with ketamine or esketamine, actually this was esketamine, some data that was shared by the Janssen Pharmaceutical Companies suggest that long-term, you see additional benefits such as reductions in suicidal attempts, suicide attempts, death by suicide, and remarkably something called all-cause mortality.

And what all-cause mortality is, is the cumulative impact of depression on your body.

You know, people as they get older, very commonly will have cardiovascular disease or risk for stroke or other kinds of medical problems.

And depression worsens that risk and worsens the outcome of treatments for those kinds of conditions.

Now, ketamine is so good, or esketamine, so good at treating these depression symptoms that it seems to reduce the impact of them on life.

So inadequately the pre-treated depression shortens life expectancy for about 10 years.

And it seems like ketamine and esketamine can reduce that shortening of life expectancy relative to other effective treatments, let alone relative to no treatment at all.

- I want to pick up on one aspect of what you brought out, which is the effect on suicide risk and that one of the effects that have been seen with ketamine and esketamine is the rapid reduction in suicide risk in addition to treating the depression, treating along with that the suicide risk.

And I'd like you to speak about that.

- You know, this has been a challenging issue to study rigorously in research.

So a number of the initial studies did describe rapid reductions in suicide ideation in patients who were getting treated with ketamine or esketamine.

What happened when Janssen went to study this very rigorously was that in order for people to be safely managed outside of the hospital with high levels of suicide risk, they greatly enriched the psychosocial treatment supports for those patients.

So everybody in their initial studies conducted by Janssen showed improvement in their suicide risk, making it very hard to detect an effect of the drug above and beyond the intensive psychosocial treatments that they got.

That's why these long-term, more real-world data are helpful because what they tell us is that in the real world of depression treatment, there's a big impact on suicide attempts and death by suicide.

- I guess it points out two things.

One is the importance of the psychosocial interventions in addition to medicine, whichever medicine is used, as well as the effect of medicine on reducing suicide risk.

- Well, Jeff, this is really part of the story about ketamine, which is that ketamine and esketamine are interventions that are embedded in an overall treatment plan.

So some patients will come and get ketamine or esketamine treatment and maybe they'll only get that esketamine treatment for a few months, and then they sort of return back to their usual kinds of treatments.

And you have to kind of be in a usual treatment for that to be possible.

Someone needs to be looking out for your overall well-being, making sure that if you have suicide thoughts or impulses that those are well managed, providing support.

You know, one of the things that sometimes can happen when people get these remarkably effective treatments, and particularly if they've been depressed for a long time, is that you have to learn how to be a healthy person again.

And the system around you has to adapt to you being healthy.

You can imagine a person who has been depressed for several years is in a family or in a workplace where people are used to that person not being very assertive, accepting whatever everybody else wants to do, not having many ideas about what they want to do.

And once they start getting better, that can rock the boat at home or at work.

And so people have to learn in a way how to get used to being themselves, fully themselves again.

It's a wonderful thing to see people getting better, but you know, it helps to get a little support in that process.

- Very important point, 'cause often the people who are receiving this type of treatment have gone through multiple episodes of depression that may have continued for many years and didn't respond to the more traditional treatment.

So they've had a long period of really suffering with all the symptoms of depression.

I want you to speak a little bit about some of the downsides because nothing is perfect and ketamine and esketamine certainly isn't.

Could you speak about some of the downsides?

- I think this is an important part of our understanding ketamine and esketamine treatment.

First, no treatment works for everyone.

So even though ketamine and esketamine are very effective for many people, for some people, it still doesn't work.

Second, when you get a therapeutic dose of ketamine or esketamine, you can get some side effects from the medication during the session.

You might feel nauseous.

Some people even may, in some sessions, throw up.

You may get a headache.

For people, generally, their blood pressure goes up about like walking up a flight of stairs.

But if you have high blood pressure to begin with, that has to be managed.

And, you know, the biggest side effect that most people are aware of is that it can change your patterns of thought and perception while the medication is in your body.

So maybe the walls will look like they're breathing in out colors, altered your sense of, your body can be altered.

You may feel that things around you are very unreal.

So some people will feel during the ketamine administration, while the drug is in their system for about a half hour or so during treatment, that that things are altered.

And for some people, that's an uncomfortable experience.

Usually, the way we manage it is by letting people know what to expect and providing support during those symptoms so that they can relax and be confident that those symptoms will go away.

The second risk, though, the one that's underappreciated as a society is that ketamine is an abuse substance.

Now, we prescribe in treatment many abuse substances.

Benzodiazepines are sometimes abused like Valium.

People get opiates for pain.

We know that they carry abuse liability.

Ketamine has some abuse liability.

And the way that we primarily manage that abuse risk is by limiting access to ketamine and esketamine to the clinic.

And when people get a access to a lot of ketamine and esketamine, there is a risk that if they were to use it as they saw fit, that they might use it in a way that's neither effective for the treatment of their depression, but in a pattern that promotes misuse.

I'll give you an example.

In a person who's been on ketamine treatment for several months, maybe they would normally get treated once every three weeks, once every four weeks with the dose of ketamine.

I have seen people and talked to people who started out getting ketamine for treatment and had a bottle to use at home who went on to use it, say, four or six times a day.

That's a very different kind of pattern of treatment.

Ketamine doesn't work nearly as well as for treating depression when you take it with that kind of frequency.

And if you develop a heavy ketamine addiction, and I have seen and met with patients who had heavy ketamine addictions in mostly in China and Taiwan.

They may take 100 times the therapeutic dose of ketamine when they take it.

And it's very bad for their brains, for their cognitive function, and for their mood.

So we try to avoid putting people in situations where the risk of ketamine addiction developing is high, like giving them lots of ketamine to take home to use.

And we try to limit exposure to ketamine in the clinic so that the abuse risk is managed as well as possible.

- So for a take home message for people watching is that if you or a loved one is considering the use of ketamine or esketamine, you wanna do that at a reputable treatment facility, whether it be at an academic institution or some other clinic that has expertise in the use of these medications.

- That's right.

And if your doctor recommends some kind of take home form of ketamine, you should really ask them about how you're gonna be protected from the risk of developing a ketamine use problem.

- Very important point.

Now, one of the things that are very interesting about ketamine is that the effect that it has, that rapid-acting antidepressant effect, really occurs subsequent to it leaving the system and it's the effect that it has on the brain.

And I'd like you to speak about really what we know about how it works.

- Yeah, you know, Jeff, this is really a great point.

And so we're so used to medications that have their beneficial effect only when the medication is in your body.

Pain medication will only work while it's in your body.

It doesn't really protect you from experiencing pain once the medication is washed out of your body.

But ketamine and esketamine work by triggering a reaction in the brain.

In a way, ketamine or esketamine trigger, recruit the brain's own resilience mechanisms in order to produce this therapeutic recovery.

And what I mean by that is, one of the interesting things about depression is that it actually affects brain structure and function.

And when you give a dose of ketamine, it reverses those effects, not only on brain function, but also brain structure.

And the antidepressant effects on brain structure last about, I mean the antidepressant effects last about as long as the impact on restoring those brain structures that are affected by depression.

And so that's why ketamine, which is a very short-acting drug, you know, a typical ketamine or esketamine treatment session lasts about two hours, can produce beneficial effects that last for many weeks because it's the brain's reaction that's the therapeutic part of ketamine.

- John, I wanna ask you about future directions in terms of our understanding of how ketamine works and potentially developing different medications based upon that mechanism of action.

- Well, this is a really very exciting area of study and there are many different paths that are being pursued.

One path that's being pursued, it takes advantage of the fact that ketamine binds to NMDA glutamate receptors, but there are actually several different subtypes of NMDA glutamate receptors.

And so there are some new drugs that are being studied that bind only to specific NMDA glutamate receptor subtypes, sometimes called the NR2B or GluN2B subtype.

Another subtype that's being studied are drugs that bind to the Glu2D and NR2C subtype of NMDA glutamate receptors.

So that's one area of study.

In our work, we've been trying to understand why is the response to ketamine time limited?

In other words, something very profound happens when people get a dose of ketamine.

I can see someone go from extremely symptomatic to, as far as we can tell, completely better after one dose in one day.

How come if a person really feels completely better that the symptoms come back?

This is something that we've been interested in a long time and we have a clue to that biology that comes out of basic neuroscience.

Alex Kwan's laboratory has shown that by day four or five when the symptoms of depressions typically start coming back in someone who's received a dose of ketamine, that the regrown connections in the brain that develop as a result of exposure to ketamine are mostly going away.

So ketamine restores brain structure, but a given dose doesn't necessarily regrow that structure permanently.

You have to keep giving additional doses to maintain that structure.

We did a study that was published a few years ago in which we gave a medication that we believe, from where we sit today, has the effect of protecting those structures from being broken down.

And the reason that we think that this drug combination protects those newly grown structures from breaking down is that instead of say 10, 20% of people still being responders to ketamine after about two weeks, we see when we pretreat with this drug, which is called rapamycin, which is a neuroprotective anti-inflammatory drug, immunosuppressant even, that the antidepressant response persists at two weeks in more like 40, 50% of people.

So if we can overcome some of the limitations of ketamine, so that is either more tolerable or potentially more effective, longer lasting, I think that we can take an already incredible treatment and increase its value to some people.

- I wanna shift gears a little bit to another type of depression that's also very important that hasn't gotten as much attention as it really should receive, which is postpartum depression, depression after giving birth.

And a new medication that really the first medication approved by FDA specific for postpartum depression that's become available.

I'd like you to speak about that.

- So you're absolutely right.

Postpartum depression is a very common problem.

It's one that people are uncomfortable talking about in the public because the child period after childbirth is a very personal, private time in people's life.

Yet it has such a big impact on the quality of life of mothers and their ability to care for their newborns.

And so it's very exciting that we have the first medication.

The first medication for postpartum depression was improved in 2019.

That was called brexanolone.

That was essentially a medication that replaced a hormone that was depleted in the body associated with childbirth.

A synthetic drug called zuranolone was more recently approved and this synthetic version of that hormone can be taken as a pill and seems to be quite effective for treating postpartum depression as well.

So we now have a medication that replaces this childbirth-related hormone and alleviates some of the symptoms of postpartum depression.

- And just to emphasize, we hear people speak about the post-birth blues that a mother can have, sometimes a father, and it can be a stressful time, but postpartum depression is more significant than that and really can affect a person's functioning.

So treating that is so important and people not suffering in silence, but seeking that help is extremely important as well.

- You're so right about highlighting the seriousness of postpartum depression.

In other words, when we talk about depression in society, we tend to think about that day when we had a really a tough time.

We don't think about an illness, which is an illness of the whole body that affects our life expectancy.

We don't think about the risk of suicide.

In this way, depression and postpartum depression, because of their overall risks for the person suffering it, are every bit as serious as any other medical condition, cancer, heart disease.

And I like to say, and as many others do, that you really can't have overall health without mental health.

- Very important point.

(dramatic music) Please join me next time when I continue my conversation with Dr. Krystal.

(dramatic music) 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.

(dramatic music)