Speaker 1: Today we're going to be speaking with Dr. John Crystal, who's a psychiatrist
and Yale University professor, maybe best known for the discovery of the rapid antidepressant
effect of ketamine in depressed patients.
Dr. Crystal, really great having you on.
I appreciate it.
Speaker 3: Really pleasure to be here today.
Speaker 1: So maybe to start with, before we talk about ketamine specifically, it'd
be great to hear from you a little bit about depression more generally.
You know, you talk to five different psychiatrists, you'll often get five, at least slightly different
answers about to what degree is depression, situational or caused by a chemical or hormonal
imbalance or some combination or it depends on the particular case.
What's your sense of our best understanding about depression at this point?
Speaker 3: Sure.
So I think there are some things that we can all agree on.
One, that it's far more common than we ever thought.
Two, that it has far more detrimental effects on people's lives than we probably had previously
appreciated.
And.
And three, that a lot of people who try to get treatment for depression find that the
treatment that they start out with isn't giving them the kind of full response that that they're
looking for.
And as a result, even for many people who are in treatment, depression continues to
take a toll on them.
And I think another thing that we would agree about depression is that it's really fundamentally
different than having a bad day.
Now, we've all had a bad day.
We've all probably had moments of despair, even.
But to sit in that state all day, every day or most of every day is a totally different
experience.
That is hard to appreciate if you haven't been through it yourself.
And so when we get to questions of causes, we have to appreciate that there are enormous.
Depression is a very broad term and there are probably many different kinds of depressions.
And unfortunately, this is one area where psychiatry has not really.
Led us to a satisfactory place.
In other words, we appreciate that there are different types of depression that people
might have, some that are purely a reaction to bereavement or getting fired or having
your marriage break up and where you have an issue or a problem that you just can't
kind of work through in it and in it takes you down into this really negative place.
But there clearly are other people who have depression that comes on, as you point out,
because of a hormonal imbalance, because of a medical problem, because of other other
kinds of things going on in the body.
And we're we know a lot more about the interplay between the body and the brain in relation
to depression that we than we ever did before.
And one of the things that we've learned is that medical problems in in the body, heart
disease, asthma, arthritis, all of these things, even obesity, can contribute to a process
in the body called inflammation, which when we think of inflammation in our joint, we
think of a sort sore joint.
When we think of inflammation in the brain, it affects the way that the circuits are regulated
and can contribute, we think, to depression.
But but there is also probably a genetic contribution.
About 30% or so of the risk for depression is is genetic.
And one of the things that you can see in some people who don't have a major life stress
and don't have a medical problem contributing is that some people out of the blue, just
part of their own make up will will experience into depression.
And that's that's really important in all of these cases.
You know, whether it's primarily stress, primarily hormonal, primarily a genetic vulnerability,
there's still we're talking about this very kind of complex interplay of a person and
their surroundings.
And so it's not surprising that we treat depression sometimes with psychotherapy, sometimes with
medications, sometimes with both.
And other things like getting a lot of social support, getting good exercise, having a healthy
diet can also help people be, make get their best chance of recovering from their depression.
Speaker 1: So before we talk about ketamine, just briefly treating depression with SSRI
arise from the research I did before our interview.
It seems like it's pretty clear that the SSRI is work better than placebo.
They don't necessarily work at numbers that are incredibly overwhelming.
It's not 90%, but it does seem better than placebo.
Is that still your understanding and what exactly are SSRI is doing in the brain?
Speaker 3: Yeah.
So so first, absolutely, SSRI is are extremely helpful for many people.
And and so I'd say if if people were just starting, they're having their first experience
of depression and they get treated with with an SSRI that they could expect about a 5050
chance of of getting better for that that SSRI.
But the reality is that that that one of the things that we've learned about depression
for many people, perhaps because of the complex interplay that we are talking about, is that
it can be a chronic or recurring disorder.
And so what sometimes happens is that people who maybe in their first episode responded
to the SSRI find that later on the medication isn't working so well.
So how SSRI is work is to raise the level of serotonin bathing the brain by preventing
its reuptake after release.
So it does increase the brain's exposure to to to to depression.
And then it's the brain's reaction to having so much serotonin around that evokes adaptive
changes in the brain that that help the regulation of mood and other aspects to function better.
And and this process is dependent on the ongoing availability of serotonin in the brain.
So if you stopped the SSRI abruptly, many people will find that their depression symptoms
will come back.
Or if you just deplete the body of serotonin, deplete the deplete the brain of serotonin,
even though people are staying on the on the SSRI medications, they may have a transient
relapse.
And that was done for research purposes to help to understand how these medications work.
So that's a general introduction to the SSRI.
Speaker 1: So let's now talk a little bit about ketamine, maybe what what is.
I mean, what were some of the early medical uses that at least it was tested for?
And then how did this start to become something that was thought of as maybe effective for
depression?
Speaker 3: Yeah, well, to me, it's a remarkable story.
So ketamine is a drug that was identified as an anesthetic medication in the in the
1960s.
And a good friend and colleague, Dr. Ed Domino, first gave this drug to people and helped
to describe its peculiar effects, which he and others called dissociative anesthesia,
which is its capacity to produce a kind of twilight state that there is people sometimes
called dissociation.
And the they didn't know how it worked when they discovered, in fact, the field of neuroscience
really didn't figure out how ketamine worked until the 1980s.
And then what we what was found out then was that ketamine works by blocking the action
of glutamate at one of its receptors called the NMDA subtype of glutamate receptor.
Now, you might say, wait, I've heard of serotonin before.
I haven't heard of glutamate.
And how is that?
Why would you think of glutamate for depression?
So this gets back to, in a way, the logic that carried us to test ketamine first in
depressed patients, which is that for a long time from, from the first identification of
these transmitters to I'd say certainly the, the, the mid to late 1990s, maybe even later,
most people thought of depression as a disorder of the norepinephrine like noradrenaline or
serotonin systems of the brain.
These are chemical systems in very primitive parts of the brain that project to the higher
centers of the brain and tune the activity of these higher brain centers.
So they reasoned, if serotonin was awry, not functioning.
Right, maybe if we give we give us a serotonin reuptake inhibiting drug.
Well, treat the symptoms of the depression by normalizing serotonin.
Well, research by several groups, including the work done here at Yale, by my colleague
Dennis Charney and Pedro de Gato, George HENNINGER and others, they showed that if you deplete
the body of serotonin, you don't produce depression.
If you deplete the body of norepinephrine, you don't produce depression.
And that the biology of depression is is is more complicated.
In some ways, this was a kind of intellectual crisis moment for the thinking about the biology
of depression and in the way that Dr. Cherney and I reasoned our way around this problem
was to say, Well, maybe if depression doesn't predominantly live in the serotonin or norepinephrine
nerve cells themselves, maybe the depression lives in the targets of of norepinephrine
and serotonin, the higher brain centers in the two main brain centers, we thought of
where the cerebral cortex, the highest executive control of our thought and behavior and emotion,
and the limbic system, the generators or drivers of emotional experience in the brain.
And and with that came a kind of an aha.
Moment, which is if.
If depression is a cortical disorder, not a brainstem disorder, then the intrinsic signaling
mechanisms of these high, higher same brain centers, the main information highways of
the higher brain centers should be involved in depression and its treatment.
And those information high higher information highways involve the neurotransmitter glutamate
as the main excitatory neurotransmitter of the cortex, like 90% of the synapses.
So we thought, let's test a drug that blocks one of these glutamate receptors.
The drug we chose to do that was Academy.
And what we found was this rapid improvement in mood within 24 hours, say, of, of a single
dose academy.
And in a large number of the people we tested.
Speaker 1: What is the dosage idea when it comes to ketamine?
Is it the type of thing that is?
It is taken daily like an SSRI.
Do the effects fall off similarly or differently?
Like is it how would it be administered?
Speaker 3: Right.
So so TIME magazine called ketamine, the anti antidepressant.
And and that is because it doesn't work like anything else we know.
First, unlike a medication that you give a little bit of the drug, you don't have much
effect of the drug and you take it every day as part of your daily life.
That's not at all what ketamine is like.
When ketamine is is you give a dose that that is high enough to be to trigger the antidepressant
response.
And and those antidepressant effects last a week or two, four in people.
And so people generally start getting two doses a week.
Then after a month or so, one dose a week, then every other week.
And so when people are maintained on it, if they need to be maintained down it, then they
may only get a dose once every three weeks or once a month.
And by spreading it out, people don't become tolerant to it.
They tend to, if anything, to become more sensitive to the antidepressant effects.
And it turns out in the long term data with ketamine, that as the version of ketamine
developed by Janssen, that it's very helpful in preventing relapse of depression and so
that it's a good long term treatment, as well as a strategy for producing a rapid antidepressant
response and to help people who haven't previously responded to antidepressant medications.
Speaker 1: Are the doses large enough when they are given that they have a sort of psychoactive
or maybe dissociative type effect.
Speaker 3: When given in the way that we end both, we in our laboratory with ketamine and
later Janssen with ketamine give ketamine.
Yes.
They tend to produce psychoactive effects.
They can make people feel spacey.
They can have altered sensory perception.
They might experience, for example, that their arm or your fingers feel longer, or they may
have a feeling that the room is breathing in or out.
And what we find is that if we prepare people for those kinds of effects, if we're with
them when they are having those experiences, and then if we can have the chance to talk
about them afterwards, then that people can both understand what's going on, not find
it very frightening and have overall a good experience.
Speaker 1: Last thing I wanted to ask about what's the sort of regulatory and legal status
right now of using ketamine in this way per the FDA?
Speaker 3: Yes.
So as ketamine, the isomer of the ketamine molecule, ketamine comes in two mirror images.
And so one of the mirror images, the isomer academy is developed by Janssen and approved
by the FDA for the treatment of treatment resistant depression and depression in the
context of suicide risk.
The standard ketamine that's used in anesthesia is approved by the FDA for anesthesia.
Right.
And what that means is that doctors can prescribe the receiver ketamine for the whatever they
want, but it is not approved by the FDA for the treatment of depression.
And that means that doctors who are prescribing this form of ketamine have some additional
liability because it's not endorsed by the FDA.
Also, the consequence of it not being approved by the FDA is that some insurance companies
only cover the Esketamine version, that the Esketamine version is given as a nasal spray.
And people take a certain number of puffs of the nasal spray that's appropriate for
them and worked out with their doctor.
And and that version of of Academy, that version of ketamine.
The ESKETAMINE is FDA approved and and increasingly covered by insurance and Medicare and Medicaid.
Speaker 1: We have been speaking with Dr. John Crystal, who is a psychiatrist and Yale
University professor.
Really interesting.
And we look forward to reading more about these these uses.
Really appreciate your time today.
Speaker 3: It's wonderful.
Wonderful to be here and to talk about this area.
So thanks for having me on.