Yale Psychiatry Grand Rounds: "Schizophrenia Therapeutics: Past, Present, and Future"

Transcript

• 00:03And David his name is
• 00:04David Lewis? I
• 00:06don't know. No.
• 00:08And,
• 00:09you know, you often I've
• 00:11been
• 00:12talking about ketamine and depression,
• 00:15but this is really an
• 00:16extraordinary moment.
• 00:17We have from two thousand
• 00:19nineteen FDA approval, the first
• 00:21mechanistically
• 00:22novel
• 00:23antidepressant.
• 00:24Two thousand twenty four,
• 00:26three weeks ago, the FDA,
• 00:29approved the first mechanistically
• 00:32novel antipsychotic
• 00:34known as CAR XT, but
• 00:37it it's, it's,
• 00:39changed its name to Cobenphi.
• 00:41And, now it's it rolls
• 00:43off the tongue.
• 00:44And,
• 00:46and this is the first
• 00:48drug that treats psychosis without
• 00:50blocking the dopamine d two
• 00:51receptor. So the theme
• 00:53of this talk today is
• 00:54really thinking about how do
• 00:56you get to a drug
• 00:58that
• 00:59treats psychosis without blocking dopamine
• 01:02d two receptors.
• 01:03How,
• 01:05how does it work?
• 01:07And how do we think
• 01:08about that biology a bit?
• 01:13Okay.
• 01:15My disclosures, I consult to
• 01:17a bunch of companies,
• 01:18number of which are developing
• 01:20antipsychotic
• 01:21medications,
• 01:22and I will make clear,
• 01:24my relationship to one company
• 01:26that's working in this space.
• 01:28And just to say
• 01:30that this lecture
• 01:32is is really,
• 01:35covers most of my career
• 01:37because one of my
• 01:39first,
• 01:40areas of work, when I
• 01:42joined the faculty was to
• 01:44try to understand
• 01:45non
• 01:48dopaminergic mechanisms in schizophrenia.
• 01:50And a lot of the
• 01:51people who, are doing some
• 01:53of the latest work,
• 01:55in,
• 01:56are are listed here, and,
• 01:58I'll try to mention them
• 01:59as well. So I'll talk
• 02:00about
• 02:01begin by talking about dopamine
• 02:03and dopamine d two receptor
• 02:05antipsychotics,
• 02:06then thinking a little bit
• 02:07about clozapine and what it
• 02:09tells
• 02:10us about some potentially novel
• 02:13mechanisms that we might pursue,
• 02:15and then,
• 02:17talk about these new, m
• 02:19one and m four muscarinic
• 02:21agonist antipsychotic
• 02:23medications
• 02:24and then try to give
• 02:25you some biological
• 02:27context for thinking about that
• 02:28biology.
• 02:30Along the way, one of
• 02:31the things that I'm going
• 02:33to try to develop
• 02:35is one that is not
• 02:36often discussed,
• 02:38in thinking about the biology
• 02:39of schizophrenia. People are are
• 02:41aware
• 02:42that there are,
• 02:44neurodevelopmental
• 02:45deficits
• 02:46and connectivity
• 02:47problems
• 02:48in schizophrenia.
• 02:50And a theme that's much
• 02:51less developed, but which which
• 02:53I'll talk about today is
• 02:54cortical disinhibition.
• 02:56And what's interesting is that
• 02:59when David Lewis does speak
• 03:01about grand rounds, he will
• 03:02he will, return to this
• 03:04scene.
• 03:06So let's let's go back
• 03:08to
• 03:09nineteen ninety six.
• 03:11And,
• 03:13and,
• 03:14the dopamine hypothesis of schizophrenia
• 03:16has been around
• 03:18for about thirty five years,
• 03:20thirty years at that point,
• 03:22thirty five years.
• 03:23And,
• 03:25Mark Lirwell, Bob, Anissa, Anissa
• 03:27Dargam,
• 03:29a number of us,
• 03:31then working with
• 03:33them, did a study where
• 03:34we,
• 03:35brought people into the SPECT
• 03:37scanner. This was not a
• 03:38PET scanner.
• 03:40And we gave them a
• 03:41high dose of amphetamine, a
• 03:43very high dose of amphetamine.
• 03:45And the and we measured
• 03:47in healthy people and people
• 03:49with schizophrenia,
• 03:50the emergence of positive or
• 03:52psychotic symptoms on the x
• 03:54axis
• 03:55and the displacement
• 03:57of a dopamine d two
• 03:59d three binding receptor ligand
• 04:02from the dopamine d two
• 04:03receptor.
• 04:05And what you can see
• 04:07here is that healthy people,
• 04:10when you even though you're
• 04:11giving them a massive dose
• 04:12of amphetamine, only displays
• 04:15about twenty percent ten percent
• 04:18of the dopamine d two
• 04:19receptor,
• 04:22ligand from its tracer
• 04:24and,
• 04:25which is an index of
• 04:26how much dopamine is being
• 04:28released.
• 04:30And and,
• 04:31you know, the main finding
• 04:33that people draw drew from
• 04:35the study is reflected here.
• 04:38Number one, that people with
• 04:40schizophrenia
• 04:41tend to release more dopamine
• 04:43in the strident
• 04:45compared to healthy people.
• 04:46And that that
• 04:48enhanced dopamine release
• 04:50was associated with psychosis.
• 04:53Although you'll see
• 04:55that amphetamine
• 04:56increased dopamine
• 04:58release in some people that
• 05:00just at the normal level
• 05:02and still
• 05:03tremendously,
• 05:05worsened their psychosis.
• 05:09But one important thing that
• 05:11became evident
• 05:12about this,
• 05:14amphetamine stimulated dopamine release in
• 05:16schizophrenia
• 05:18was that the more you
• 05:20got worse on amphetamine, the
• 05:22more dopamine,
• 05:23that you released when amphetamine
• 05:25was administered, amphetamine being a
• 05:27drug that releases dopamine, of
• 05:29course,
• 05:30the better you tended to
• 05:32respond to dopamine d two
• 05:34receptor blocking antipsychotics.
• 05:36And I'm gonna come back
• 05:38to this idea in just
• 05:39a minute that
• 05:42that anti d two blocking
• 05:43antipsychotics
• 05:44don't treat psychosis,
• 05:46what they do is normalize
• 05:48the extent to which dopamine
• 05:50d two receptors
• 05:51are stimulated
• 05:52under conditions where dopamine receptors
• 05:55are overstimulated.
• 05:57And so,
• 05:59and thereby, if you're overstimulated
• 06:02in psychotic, dopamine d two
• 06:04receptor blockade can be therapeutic.
• 06:07But
• 06:08there,
• 06:09there's something
• 06:13about the way that I
• 06:14look at these data that
• 06:16seemed always very important to
• 06:18me.
• 06:19The first is you can
• 06:20see that there are a
• 06:22lot of people with schizophrenia
• 06:25whose dopamine release under amphetamine
• 06:28is less
• 06:30than that mean for healthy
• 06:31subjects.
• 06:33Second thing you can see,
• 06:34which is kind of shocking
• 06:36and surprising for you,
• 06:38is that there's a whole
• 06:39group of people that not
• 06:41only doesn't have
• 06:43worsening of psychosis when amphetamine
• 06:45is administered,
• 06:47they actually have a reduction
• 06:49in the severity of their
• 06:50psychosis when amphetamine is administered.
• 06:53And,
• 06:56right from
• 06:57the outset,
• 06:58you'd have to say looking
• 07:00at these data while the
• 07:02dopamine hypothesis
• 07:03of schizophrenia
• 07:05was affirmed in a certain
• 07:07group of people with schizophrenia.
• 07:09That right from these data,
• 07:12we should have assumed
• 07:13that there was a non
• 07:16dopamine, non d two
• 07:18hypothesis of schizophrenia
• 07:20in the very
• 07:21same sample.
• 07:23Now
• 07:24one of the things that
• 07:26that's very striking about amphetamine
• 07:30is that a lot of
• 07:31people take amphetamine and don't
• 07:33get psychotic.
• 07:34So how can it be
• 07:36that people with schizophrenia
• 07:38get robustly psychotic when they
• 07:40get amphetamine, but healthy people
• 07:42may not get psychotic at
• 07:44all when given the same
• 07:45dose?
• 07:46And what I'm going to
• 07:48suggest is that one of
• 07:50the
• 07:51potential dynamics that might be
• 07:53relevant there is what the
• 07:55background what your background biology
• 07:57is when you get amphetamine.
• 08:00And a particular dynamic related
• 08:02to,
• 08:03but cortical,
• 08:05disinhibition
• 08:07might be relevant. In other
• 08:09words, if you have a
• 08:10reduction
• 08:12in cortical GABA function,
• 08:15which disinhibits and increases the
• 08:18propensity
• 08:20of
• 08:20the cortex, broadly speaking, hippocampus
• 08:23cortex, etcetera,
• 08:25to drive,
• 08:27glutamate release in subcortical structures.
• 08:30One of the things you
• 08:31might get when you get
• 08:33get a dose of amphetamine
• 08:35is a hyper release of
• 08:36dopamine
• 08:37and an enhanced,
• 08:40vulnerability
• 08:41to becoming psychotic
• 08:42when you get a dose
• 08:43of amphetamine.
• 08:45To test that hypothesis
• 08:48a number of years ago
• 08:49now with Cyril D'Souza,
• 08:51Kyung Ahn,
• 08:53and others
• 08:54at the VA,
• 08:56we did a study
• 08:57where
• 08:58we tried to test that
• 09:00hypothesis
• 09:01by creating a GABA deficit
• 09:03in the brain.
• 09:04And we created that GABA
• 09:06GABA deficit to try to
• 09:07mimic cortical disinhibition,
• 09:09GABA being the inhibitory
• 09:11transmitter.
• 09:12And so we took a
• 09:14group of people with healthy
• 09:15subject. We created a GABA
• 09:17deficit by giving a low
• 09:19dose of a drug called
• 09:20iomazinil,
• 09:22which is a what's called
• 09:23a partial inverse agonist. In
• 09:25other words, it it reduces
• 09:27the function
• 09:28of GABA a receptors in
• 09:30the brain.
• 09:31And we looked at the
• 09:33response to amphetamine,
• 09:35and this a lower dose
• 09:36of amphetamine, in fact, the
• 09:39iomazinil and the combination.
• 09:41And what you can see
• 09:42in this group of healthy
• 09:43subjects is that iomazinil and
• 09:45gab and I, amphetamine by
• 09:47itself did not really produce
• 09:49a meaningful,
• 09:50emergence of any psychotic symptoms.
• 09:52But when we created the
• 09:54GABA deficit and then we
• 09:56gave amphetamine,
• 09:57voila,
• 09:58the healthy subjects
• 10:00are getting more psychotic or
• 10:02low mild psychosis, but a
• 10:04transient
• 10:05mild psychosis.
• 10:07So
• 10:08this idea of cortical disinhibition
• 10:10or
• 10:12deficits in in inhibitory tone,
• 10:14in this case, broadly in
• 10:15the brain,
• 10:16being related
• 10:18so they don't have your
• 10:20graph.
• 10:21Okay.
• 10:22Sorry.
• 10:24Got it. Did I have
• 10:26my family travel pictures up
• 10:27there?
• 10:32Was supported by this idea.
• 10:33In other words, if you
• 10:34have a deficit, inhibitory deficit
• 10:36in the brain not to
• 10:38find what it is here
• 10:40and you get amphetamine, you're
• 10:41more likely to get psychosis
• 10:43mimicking what might be broad
• 10:46inhibitory deficits,
• 10:48that potentially are associated with
• 10:51schizophrenia.
• 10:52Now as I mentioned,
• 10:55antipsychotics
• 10:56don't treat symptoms. They normalize
• 10:58dopamine receptor stimulation.
• 11:00And one of the signatures
• 11:02of that normalization
• 11:03is that it you dose
• 11:04antipsychotics
• 11:06so that endogenous,
• 11:08dopamine,
• 11:09is back in the normal
• 11:10level. And that turns out
• 11:12to be for most antagonist
• 11:15dopamine d two receptor antagonists,
• 11:17somewhere between sixty and eighty
• 11:19percent occupancy of the dopamine
• 11:21d two receptor. If you
• 11:22go lower, the drugs don't
• 11:24work. If you go higher,
• 11:25you don't get more efficacy,
• 11:28but you do create
• 11:29something that looks
• 11:31like a dopamine deficits in
• 11:32terms of Parkinson's disease. Right?
• 11:34You get extra pyramidal symptoms.
• 11:36So
• 11:37so
• 11:38we use these drugs to
• 11:40normalize
• 11:42dopamine d two receptor function.
• 11:45One of the ways that
• 11:47we can
• 11:48affirm that idea
• 11:50is to look what happens
• 11:51if we give a partial
• 11:53agonist of the dopamine d
• 11:54two receptor like aripiprazole or
• 11:56bragripiprazole.
• 11:58These are drugs that stimulate,
• 12:01dopamine d two receptors with
• 12:03about thirty percent
• 12:05of the
• 12:06activity of dopamine.
• 12:08And so
• 12:10in order to get
• 12:11the equivalent of sixty to
• 12:13eighty percent blockade of dopamine
• 12:15d two receptor function with
• 12:17a partial agonist, And this
• 12:18is the work of Anissa
• 12:20Abi Darham, who was here
• 12:21at Yale for for her
• 12:23training and, a number of
• 12:25years on the faculty.
• 12:27You have to use eighty
• 12:28to hundred percent
• 12:30occupancy of dopamine d two
• 12:32receptors to same get the
• 12:32same clinical efficacy. So so
• 12:33we're using these drugs to
• 12:34normalize
• 12:35dopamine d two receptors. So
• 12:36what's
• 12:38the problem?
• 12:44The problem, as we all
• 12:46know, is that these drugs
• 12:47are not as effective as
• 12:49we'd like them to be.
• 12:50If you look at the
• 12:51clinical trials in schizophrenia,
• 12:54do a meta analysis as
• 12:56has been done by Stefan
• 12:57Leuchtt,
• 12:58What you see is that
• 12:59in these trials,
• 13:01fifty percent of,
• 13:05fifty percent of patients,
• 13:10achieve,
• 13:11remission I'm sorry, achieve a
• 13:14twenty percent reduction
• 13:16in treatment severity. Fifty percent
• 13:18of patients achieve a twenty
• 13:20percent reduction treatment severity.
• 13:22But in depression, twenty percent
• 13:24reduction in treatment severity is
• 13:26not considered clinical response.
• 13:28In clinical in depression
• 13:30and most other psychiatric disorders,
• 13:33the threshold for a clinical
• 13:35response is fifty
• 13:37percent reduction in symptoms.
• 13:39And you see only
• 13:41twenty percent of patients with
• 13:43schizophrenia
• 13:44achieve a fifty percent reduction
• 13:47in the severity of their
• 13:48schizophrenia symptoms. And that twenty
• 13:51percent is only ten percent
• 13:53better than the group getting
• 13:55placebo.
• 13:56So
• 13:58so our drugs
• 14:00that we know help so
• 14:02many people
• 14:03develop productive lives out of
• 14:05the hospital,
• 14:07are doing so by incrementally
• 14:10reducing the severity of their
• 14:12schizophrenia symptoms.
• 14:15And if you look at
• 14:16it another way, which is
• 14:18stable remission,
• 14:19there was a a a
• 14:21study that compared long term
• 14:23outcomes, twenty five year outcomes
• 14:26in,
• 14:26about a hundred and fifty
• 14:28nine schizophrenia patients to
• 14:30a hundred and fifty two
• 14:32patients with other psychotic disorders.
• 14:35Out of their hundred and
• 14:36fifty nine patients,
• 14:38zero patients with schizophrenia
• 14:40achieved stable remission
• 14:42of their illness throughout their
• 14:44careers.
• 14:46And,
• 14:47almost fifty percent
• 14:49never achieved remission
• 14:52over twenty five years of
• 14:53their schizophrenia.
• 14:54And remission criteria is no
• 14:57symptom of schizophrenia more than
• 14:59mild in severity.
• 15:01So
• 15:02so
• 15:04whether you look in the
• 15:04short run like the Loechterdal
• 15:07meta analysis or the short
• 15:08term clinical trials
• 15:10or you look in the
• 15:11long run,
• 15:12as the, Tramato paper,
• 15:16looks, there's,
• 15:17as we say, room for
• 15:18improvement.
• 15:21So why is there room
• 15:22for improvement?
• 15:24Well,
• 15:25one of the one of
• 15:26the reasons that there's probably
• 15:28room for improvement is that
• 15:29biology of schizophrenia is a
• 15:31lot more complicated than dose.
• 15:34But another reason there's room
• 15:36for improvement
• 15:37is that,
• 15:40there's only one region in
• 15:42the brain that has
• 15:43shows replicable
• 15:45dopamine hyperactivity.
• 15:47And that is a small
• 15:49area
• 15:50that we call the associative
• 15:52striatum, which includes the head
• 15:53of the caudate,
• 15:55where
• 15:57in study after study, you
• 15:58see increased dopamine metabolism, you
• 16:00see increased dopamine release,
• 16:02etcetera, etcetera.
• 16:04And in every other region
• 16:06of the brain,
• 16:08frontal cortex, ventral striatum, temporal
• 16:11cortex,
• 16:12midbrain,
• 16:13thalamus,
• 16:15either you see no change
• 16:16in dopamine or you see
• 16:18a decrease.
• 16:19And so every time you
• 16:21prescribe
• 16:21a dopamine d two receptor
• 16:23blocking drug to normalize
• 16:26the level of dopamine d
• 16:28two receptor stimulation in the
• 16:29associative stratum,
• 16:31you're creating a dopamine deficit
• 16:34dopamine d two receptor in
• 16:36the entire
• 16:37rest of the brain.
• 16:39And
• 16:40people have long thought
• 16:43that these,
• 16:46these side effects
• 16:48arising from
• 16:49not over blockade of straddle
• 16:52dopamine d two receptors,
• 16:54but the effects of,
• 16:56blocking dopamine in the rest
• 16:57of the brain may account
• 16:59for some of the limitations
• 17:01in the effectiveness
• 17:02of of antipsychotic
• 17:04medication,
• 17:05including,
• 17:08blunting of expression
• 17:10of emotion,
• 17:12appearing to worsen the negative
• 17:14symptoms of schizophrenia,
• 17:17not to mention medical risks
• 17:19like weight gain and exacerbating
• 17:21insulin resistance.
• 17:24So
• 17:25when I was
• 17:28twenty
• 17:29eight,
• 17:31six,
• 17:33I thought
• 17:35there's more to there's gotta
• 17:37be more than dopamine.
• 17:40And,
• 17:41and what I wanted to
• 17:42do was to probe the
• 17:44the
• 17:45the intrinsic circuitry,
• 17:48receptor circuitry
• 17:50of the cortex
• 17:51in schizophrenia.
• 17:54Little problem,
• 17:56no brain imaging.
• 17:58No PET, no SPECT,
• 18:00no fMRI,
• 18:01not even really MRI
• 18:03at that time. CT scans,
• 18:05you could do by then.
• 18:08And,
• 18:09so how could we probe
• 18:11glutamate synaptic function
• 18:13when we had
• 18:15such limited technology to look
• 18:17at this?
• 18:18So I thought we could
• 18:19use ketamine.
• 18:21And, I remember talking about
• 18:23this
• 18:24with, Dennis Charney at the
• 18:26VA,
• 18:28wondering whether
• 18:30he was going to think
• 18:31I was dissociating.
• 18:34When I proposed that, he
• 18:35was quite enthusiastic
• 18:37about testing ketamine effects in
• 18:39in healthy people.
• 18:41And I got,
• 18:42as advisers to this study,
• 18:47Elliot Looby,
• 18:48who had given
• 18:50PCP to schizophrenia patients, published
• 18:53the first study in nineteen
• 18:54fifty nine.
• 18:56And and Ed Domino,
• 18:58who was the first person
• 18:59to give ketamine,
• 19:01to humans as to help
• 19:03me design the study in
• 19:04a way that was safe.
• 19:07And,
• 19:08and what we found with
• 19:09ketamine was that for the
• 19:11first time that we had
• 19:12this
• 19:13syndrome emerge,
• 19:15obviously, with dissociative symptoms as
• 19:17as is often highlighted,
• 19:19but also with mild psychotic
• 19:21symptoms,
• 19:23negative symptoms, and cognitive impairments
• 19:26that resembled in some way,
• 19:28schizophrenia.
• 19:30So
• 19:31so
• 19:32this was really interesting. You
• 19:34had a drug that looked
• 19:35a lot like
• 19:37a syndrome that looked a
• 19:38little bit like schizophrenia.
• 19:40What did it have to
• 19:41do with dopamine?
• 19:44And I spent
• 19:45I was gonna say wasted,
• 19:47but I invested,
• 19:49a number of years
• 19:50trying to figure out what
• 19:52the relationship
• 19:54of of ketamine and and,
• 19:56dopamine
• 19:58was. And the answer was
• 19:59not much.
• 20:01We tried to block the
• 20:03psychogenic
• 20:04effects of ketamine with haloperidol.
• 20:08As you can see on
• 20:09the left,
• 20:10Haloperidol
• 20:11at a dose of five
• 20:12milligrams, which was enough in
• 20:13some people to get evanescent
• 20:15extrapyramidal
• 20:16symptoms, did nothing
• 20:18to the ketamine psychosis.
• 20:20We thought, okay. Well, maybe
• 20:22we're going at it the
• 20:23wrong way. Let's give them
• 20:25amphetamine.
• 20:26And we gave them the
• 20:28same amp high amphetamine dose
• 20:30that we use in the
• 20:31PET studies and SPECT studies.
• 20:33And we couldn't make the
• 20:35ketamine psychosis
• 20:36worse. In fact, we gave
• 20:38so much amphetamine
• 20:39that some of the healthy
• 20:41subjects started to have,
• 20:43evanescent psychotic symptoms just from
• 20:45the,
• 20:46amphetamine
• 20:47itself, paranoia, irritability, blah blah
• 20:49blah.
• 20:50So
• 20:52so
• 20:53by certainly, we had the
• 20:55beginnings of this amphetamine data
• 20:57in the early two thousands.
• 20:59Certainly, by by two thousand,
• 21:01we knew
• 21:02that the ketamine psychosis,
• 21:05if we were if we
• 21:06were gonna follow the trail,
• 21:08it wasn't gonna lead us
• 21:10to better understanding of how
• 21:11dopamine d two receptor antagonists
• 21:14would work.
• 21:15It might lead us to
• 21:17drugs that could treat psychosis
• 21:19without blocking dopamine d two
• 21:21receptors, and it might even
• 21:22lead us to drugs
• 21:23that were effective for psychosis
• 21:25when dopamine
• 21:26d two receptor drugs were
• 21:28ineffective.
• 21:30Now,
• 21:32historically,
• 21:34there were already
• 21:37two drugs two classes of
• 21:39drugs that have been tried.
• 21:40Reserpine,
• 21:41which is a monoamine
• 21:43depleting drug,
• 21:44which was used as an
• 21:46antipsychotic
• 21:47medication until the
• 21:49until the, antipsychotics
• 21:51became available.
• 21:52It had tolerability problems, but
• 21:54it also had somewhat limited
• 21:55efficacy,
• 21:57at least as the literature
• 21:58suggests.
• 21:59And then another so roserpine
• 22:02was like the anti embedding.
• 22:04And another class of drug
• 22:05was like the anti LSD.
• 22:07These were serotonin two way
• 22:09inverse agonists,
• 22:10drugs that had names like
• 22:13m one hundred nine zero
• 22:14seven,
• 22:15pimavanserin,
• 22:16amparaside,
• 22:18phenanserin,
• 22:20etcetera, etcetera,
• 22:21retanserin,
• 22:22kitanserin.
• 22:23These drugs
• 22:24also were put forward to
• 22:25study, and they didn't work.
• 22:28Recently, two,
• 22:30different mechanisms have proposed, one
• 22:33tar one agonism, which hasn't
• 22:35shown replicable efficacy, and so
• 22:36I'm not really gonna talk
• 22:37about it today.
• 22:39And the other one,
• 22:40muscarinic
• 22:41m four agonism, which is
• 22:42gonna be kind of the
• 22:44focus of the talk.
• 22:46And,
• 22:50you know,
• 22:51muscarinic
• 22:53acetylcholine and apologize for Marina
• 22:55because every time I go
• 22:56on and on about Marina
• 22:58about glutamate, Marina reminds me
• 22:59that that acetylcholine is also
• 23:02extremely important.
• 23:03And and,
• 23:05the the thing about
• 23:07muscarinic,
• 23:09signaling in schizophrenia
• 23:10is that we had long
• 23:11had postmortem data from Brian
• 23:14Dean who's works in Melbourne,
• 23:16Australia
• 23:17that suggested in many regions
• 23:19of the brain, prefrontal cortex,
• 23:20striatum, hippocampus,
• 23:22and parietal cortex, you saw
• 23:24reduced,
• 23:26levels of m one and
• 23:27m four receptors.
• 23:29Now this wasn't an antipsychotic
• 23:31artifact
• 23:32because the anti anticholinergic,
• 23:34antipsychotics
• 23:36raise,
• 23:37the levels of these receptors
• 23:39and tend to reduce
• 23:41the
• 23:42differences between patients and healthy
• 23:44subjects.
• 23:48And it's not because the
• 23:49brain's not making enough,
• 23:51acetylcholine because the enzyme, choline
• 23:54acetyltransferase,
• 23:55is expressed at normal levels
• 23:57throughout the whole brain except
• 23:59possibly in the brainstem.
• 24:01And,
• 24:03so
• 24:04there's something funky going on
• 24:07with muscarinic m one and
• 24:08m four receptors that is
• 24:09not understood,
• 24:11which if anything
• 24:12might be enhanced
• 24:13acetylcholine
• 24:14release.
• 24:16Well, you could say, well,
• 24:18that's
• 24:19that's
• 24:20it's just postmortem.
• 24:22And what's really neat, it
• 24:24was with our pet center,
• 24:26Rajiv Radhakrishnan,
• 24:28Cyril D'Souza, and their collaborators
• 24:30have shown in vivo using
• 24:32a radio tracer that binds
• 24:34to the m one receptor
• 24:35in multiple regions of the
• 24:36brain, reduced ligand binding, suggesting
• 24:39that the postmortem findings are
• 24:41really are relevant
• 24:43to what we're seeing in
• 24:44vivo. So we have to
• 24:46we have to,
• 24:48in the background,
• 24:49keep in mind as I
• 24:50talk about these medications the
• 24:52possibility
• 24:54that that they are addressing,
• 24:56a cholinergic,
• 24:59signaling abnormality that we do
• 25:00not yet understand.
• 25:05But but remarkably,
• 25:07it wasn't the intrinsic
• 25:09abnormality in muscarinic
• 25:11signaling in the brain in
• 25:12the postmortem
• 25:13that led people to,
• 25:16to identify,
• 25:18drugs acting on m one
• 25:19four,
• 25:21as a treatment for schizophrenia.
• 25:25One of the threads and
• 25:26it was I I was
• 25:27just talking earlier this week
• 25:28to the guy who
• 25:30who did the first study.
• 25:31So,
• 25:33it it it's a very
• 25:34vivid story for me. One
• 25:37clue that they followed
• 25:39was clozapine.
• 25:41Now when you look at
• 25:42the effectiveness of our antipsychotic
• 25:44medications,
• 25:45they all look pretty similar
• 25:47with one drug
• 25:48standing out, clozapine,
• 25:50as being
• 25:52more effective
• 25:54than other,
• 25:56antipsychotic
• 25:57medications.
• 25:58And there's one thing about
• 26:00clozapine
• 26:01that people often forget.
• 26:03Now you remember,
• 26:05antipsychotic
• 26:05medications
• 26:07work all d two blocking
• 26:09antipsychotic
• 26:09medications, which includes
• 26:11the class that clozapine is
• 26:13in, work between
• 26:15sixty and eighty percent occupancy,
• 26:18except for close-up.
• 26:20Oh, wait. I'm out of
• 26:22there we go.
• 26:23That's weird. My
• 26:26my
• 26:26screen and your screen are
• 26:28a little different.
• 26:30I hope I have. Alright.
• 26:32Okay.
• 26:33So
• 26:34clozapine
• 26:35is effective
• 26:36with forty
• 26:38to sixty percent occupants.
• 26:40It's the only antipsychotic
• 26:42that that is effective with
• 26:44lower levels of d two
• 26:46receptor occupancy.
• 26:48And nobody knew why.
• 26:51I'm not sure we still
• 26:53know why. But one interesting
• 26:55thing about clozapine
• 26:57and its metabolite, desmethylclozapine,
• 27:00is,
• 27:00clozapine is a partial agonist
• 27:03at the m four muscarinic
• 27:05acetylcholine receptor and at the
• 27:08m one muscarinic and its
• 27:10metabolite also at the muscarinic
• 27:11m four.
• 27:12That's why when all the
• 27:14other antipsychotic may medications
• 27:17give patients dry mouth,
• 27:19with clozapine,
• 27:21you get hypersalivation.
• 27:23For example, the salivary glands
• 27:25have a lot of m
• 27:26one receptors.
• 27:27You can see that on
• 27:28PET scans of m one.
• 27:29And so if you stimulate
• 27:31m one receptors, you get,
• 27:33you get increased salivation.
• 27:36So
• 27:37so
• 27:38these drugs
• 27:39are are having
• 27:41a little bit different,
• 27:43efficacy.
• 27:45Now
• 27:47in in parallel with,
• 27:50there was a lot of
• 27:51interest in how clozapine worked
• 27:53at Lilly Pharmaceuticals because they
• 27:55were in the process
• 27:56of developing an alternative to
• 27:58clozapine,
• 27:59which was modeled both on
• 28:01the pharmacology and the chemical
• 28:02structure of clozapine. And that,
• 28:04of course, is olanzapine.
• 28:07But they were also
• 28:09developing trying to develop treatments
• 28:11for Alzheimer's disease. And they
• 28:13had a drug
• 28:14called zanomelene,
• 28:16which they called a selective
• 28:18muscarinic receptor agonist.
• 28:21I think they mean by
• 28:22that
• 28:23muscarinic versus other receptors
• 28:25because zanomelene
• 28:28prefer is preferential binding to
• 28:30m one and m four
• 28:32muscarinic receptors, but it also
• 28:34binds to several other muscarinic
• 28:36receptors with lower affinity.
• 28:40So,
• 28:41but it it showed some
• 28:43promise
• 28:44as a treatment for Alzheimer's
• 28:45disease, but it was utterly
• 28:47intolerable,
• 28:48And so it was not
• 28:49developed.
• 28:51So
• 28:53but when they were
• 28:55studying zenomelene
• 28:56for,
• 28:57the treatment of
• 28:59Alzheimer's disease,
• 29:01Kurt Rasmussen,
• 29:02who used to be here
• 29:03working in George Agajanian's lab,
• 29:06did a study with zenomelene
• 29:08in which he showed
• 29:09that at a dose that
• 29:10was sort of in the
• 29:11effective dose range, that you
• 29:14completely shut down the activity
• 29:16of the ventral
• 29:17mental area, a subgroup of
• 29:19the dopamine nerve cells in
• 29:20the brain.
• 29:22And that made Anantha Shekar
• 29:25think,
• 29:28ah, we should test zenomelene
• 29:31in patients with schizophrenia.
• 29:34And so and and Anantha
• 29:36is now the dean at
• 29:37the University of Pittsburgh where
• 29:39David Lewis works.
• 29:41The
• 29:43the,
• 29:45he did a study which
• 29:46was published in two thousand
• 29:47eight
• 29:48in which he gave zenomelene,
• 29:50this agonist,
• 29:51to people with schizophrenia,
• 29:54parallel group design, placebo control
• 29:56design,
• 29:57in which in their short
• 29:59trial,
• 30:00they saw evidence of antipsychotic
• 30:02efficacy,
• 30:03which is thought to be
• 30:05associated
• 30:05with,
• 30:08m four.
• 30:10And evidence of improved cognitive
• 30:13performance, which may be a
• 30:15signal of m one or
• 30:17m one and m four.
• 30:19The problem was
• 30:20zanomaline
• 30:22made people throw up,
• 30:25and caused significant GI distress
• 30:27in addition to producing salivation
• 30:29and sweating. And so it
• 30:31was utterly intolerable in the
• 30:33patients with schizophrenia as it
• 30:34had been in the
• 30:36dementia patients.
• 30:38And so
• 30:39it sat on the shelf,
• 30:42the shelf of Steve Paul's
• 30:44mind
• 30:45until
• 30:46Steve Paul created
• 30:48a company
• 30:49called,
• 30:50Karuna Pharmaceuticals.
• 30:52And what Karuna Pharmaceuticals
• 30:54did was to combine
• 30:57zanomelene
• 30:58with a drug that blocked
• 31:00the peripheral side effects of
• 31:02muscarinic receptor stimulation called trospium.
• 31:06And they called this combination
• 31:08of,
• 31:10of
• 31:11zanomelene,
• 31:12entrosplum,
• 31:14CAR XT,
• 31:15and when it got approved
• 31:16by the FDA,
• 31:18got the name Cabenfe.
• 31:20And in twenty twenty one,
• 31:22they published the first study
• 31:24with CAR XT.
• 31:26And the and the senior
• 31:27author on that paper was
• 31:29a guy named Alan Breyer
• 31:31who trained here at Yale
• 31:34and, then,
• 31:36moved on to have his
• 31:37career,
• 31:39at Lilly and and IMH
• 31:41in Indiana.
• 31:43And in this first study
• 31:45that they published,
• 31:46the thing that struck
• 31:48me and probably everyone who
• 31:50has seen this data
• 31:51is that,
• 31:54this is a drug that
• 31:55seems to be quite effective
• 31:56for psychosis,
• 31:58but it also seems to
• 31:59be quite effective
• 32:00for negative symptoms. In fact,
• 32:03relative to the magnitude of
• 32:05the psychotic,
• 32:06antipsychotic
• 32:06effect, its negative
• 32:08symptom
• 32:09efficacy was really quite striking.
• 32:12And the scuttlebutt
• 32:15was that when taking these
• 32:16medications, people didn't feel drugged
• 32:20or dulled
• 32:21by the medication.
• 32:23And and,
• 32:27and thought about it favorably.
• 32:29Overall, there was no significant
• 32:32effect of CAR XT in
• 32:33the trial.
• 32:35And that to me is
• 32:38something I'm confident of.
• 32:41However, they did a secondary
• 32:42analysis,
• 32:43which yields these very, very
• 32:45intriguing data,
• 32:47which is that if you
• 32:48had were in the study
• 32:49and you had a more
• 32:51severe cognitive impairment greater than
• 32:53one standard deviation
• 32:55below the,
• 32:56normative values, then there was
• 32:58a hint
• 33:00of a of a what
• 33:01looks like a robust
• 33:03procognitive
• 33:04effect on their on their
• 33:05cognitive screen.
• 33:08Why there should be a
• 33:10sharp demarcation at one standard
• 33:12deviation is not clear to
• 33:14me.
• 33:14And the fact that it's
• 33:15a post hoc analysis where
• 33:17they could see the data
• 33:18and potentially cut the data
• 33:20at different
• 33:21points,
• 33:22before reporting them. I think
• 33:24we have to take these
• 33:25data with a grain of
• 33:26salt.
• 33:27But
• 33:28since we saw a cognitive
• 33:30signal in those initials, in
• 33:32the nomaline study,
• 33:34and seeing a hint of
• 33:36it here makes it very
• 33:37interesting.
• 33:40The other thing that's kind
• 33:41of interesting about CAR XT
• 33:43is it's
• 33:44overall reasonably tolerable.
• 33:47But because it's a receptor
• 33:49stimulator combined with a receptor
• 33:50blocker,
• 33:51you get some side effects
• 33:53associated with the stimulator
• 33:55and some side effects associated
• 33:57with the blocker. It's not
• 33:59you it's impossible to get
• 34:00a perfect
• 34:01canceling out.
• 34:03And so there is a
• 34:03little bit of a side
• 34:04effect,
• 34:05burden here.
• 34:10As you probably figured out,
• 34:12because it got FDA approval,
• 34:14the phase three studies, emergent
• 34:16two and emergent three,
• 34:18were also robustly positive, although
• 34:21the negative symptom effect in
• 34:22emergent three was a little
• 34:24bit smaller.
• 34:28So then
• 34:30another company,
• 34:33with a drug called imraclidine.
• 34:35Where did imraclidine
• 34:36come from?
• 34:37Imraclidine was
• 34:39a an m four
• 34:41positive
• 34:42allosteric
• 34:43modulator.
• 34:44Not a stimulator,
• 34:46but it enhances the effectiveness
• 34:48of acetylcholine
• 34:49at the muscarinic m four
• 34:51receptor.
• 34:52Extremely selective. Whereas CAR XT
• 34:55binds to all the muscarinic
• 34:56receptors, particularly m one m
• 34:58four, this just binds
• 35:00specifically to m four.
• 35:03And,
• 35:04so you it's it's very
• 35:05well tolerated.
• 35:06It was a drug developed
• 35:08by Pfizer Pharmaceuticals.
• 35:09And then when Pfizer Pharmaceuticals
• 35:11shut down their,
• 35:14their neuroscience program, the drug
• 35:16was out licensed to a
• 35:18little,
• 35:19well, big
• 35:20startup company called Cerevel,
• 35:23which was just purchased by
• 35:24AbbVie for
• 35:26almost ten billion dollars.
• 35:28So who's laughing now, Pfizer?
• 35:30Right?
• 35:34So
• 35:35so,
• 35:37so one point I'd like
• 35:38to make is I'd like
• 35:39to highlight our alumni.
• 35:42Phil Iredale,
• 35:43who did his training here
• 35:45was even on the faculty,
• 35:47I think in the child
• 35:48study center and in
• 35:50psychiatry,
• 35:51was is the leader of
• 35:53the neuroscience program at CerroVal.
• 35:56And Ray Sanchez, a graduate
• 35:58of our psychiatry residency program,
• 36:01became the chief medical officer
• 36:04at,
• 36:05Cervel. And it was really
• 36:07interesting to consult,
• 36:09to this program,
• 36:11because
• 36:12their
• 36:13phase one b phase one
• 36:15b is usually
• 36:17never reported publicly. Usually, it's
• 36:19not very interesting.
• 36:21But the phase one b
• 36:22data,
• 36:24of imaraclidine,
• 36:26this positive allosteric modulator for
• 36:28m four receptors,
• 36:29recapitulated
• 36:30at thirty milligrams a day,
• 36:32recapitulated the clinical profile that
• 36:34we saw
• 36:35with,
• 36:37CAR XT
• 36:38and,
• 36:39and, Kobenfe.
• 36:41So that's really interesting because
• 36:43this is an extremely
• 36:45selective
• 36:46compound.
• 36:47And its clinical profile looks
• 36:50a lot like this drug,
• 36:51CAR XT, that binds to
• 36:52all these other receptors.
• 36:54And
• 36:55so
• 36:56what that raises as a
• 36:58possibility
• 36:59is that the effect on
• 37:01positive symptoms and negative symptoms
• 37:04is largely
• 37:06accounted for
• 37:07by the stimulation
• 37:09of the m four receptor.
• 37:11And and the fact that
• 37:13you have two different drugs
• 37:14binding on these receptors
• 37:16in two different ways,
• 37:20suggests that it's real,
• 37:22that this is a real
• 37:24clinical effect.
• 37:25They're actually,
• 37:27well, anyway,
• 37:30emaclidine
• 37:31and CAR XT,
• 37:33in terms of medical management,
• 37:35the thing you watch most
• 37:36is blood pressure increases,
• 37:38and that tolerates out over
• 37:39time.
• 37:41There are at least three
• 37:42other m four drugs being
• 37:44developed, one by Neurocrine
• 37:46that has positive data at
• 37:47twenty milligrams,
• 37:49Maplight, a company created by
• 37:51Karl Deiserroth and Rob Malenka,
• 37:54and Nomura,
• 37:55company,
• 37:56in on the West Coast.
• 37:58So
• 38:00it looks like m four
• 38:01drugs are gonna be
• 38:03a whole class of drugs,
• 38:06some with varying degrees of
• 38:07stimulating the m one receptor.
• 38:09And I'll talk a little
• 38:10bit about what m one
• 38:12might bring to the table.
• 38:16And they could have a
• 38:17huge impact on the treatment
• 38:18of schizophrenia
• 38:19because you don't feel like
• 38:21you're drugged. You don't feel
• 38:22like you're dull.
• 38:24Your your negative symptoms get
• 38:25better and your psychosis is
• 38:27reasonably well managed.
• 38:29We do not yet know
• 38:30how relatively
• 38:32effective these medications are in
• 38:34relation to the standard medications.
• 38:38And we do not know
• 38:39if these drugs work for
• 38:41treatment resistant symptoms
• 38:44of of schizophrenia. In other
• 38:45words, does is it are
• 38:46these medications
• 38:48helpful to add on to
• 38:49standard medications when there are
• 38:51residual symptoms?
• 38:54But this is a huge,
• 38:56huge
• 38:57step forward, particularly
• 38:59when we think about tolerability
• 39:01as a key driver adherence
• 39:02to medication.
• 39:04Getting people to a medication
• 39:06they want to take
• 39:08as opposed to a medication
• 39:09they feel like they have
• 39:10to take
• 39:11would be an enormous
• 39:13advantage in psychiatry.
• 39:15So why
• 39:17why
• 39:18would an m four or
• 39:19m one,
• 39:22agonist have antipsychotic
• 39:24activity?
• 39:25So
• 39:26short answer, we we don't
• 39:28know.
• 39:29So I'm gonna tell you
• 39:31a story,
• 39:32and parts of it are
• 39:33gonna be relatively more or
• 39:35relatively less plausible.
• 39:37And you can decide for
• 39:39yourself which parts those are.
• 39:41So let's take a a
• 39:42step back and think about
• 39:44schizophrenia at a very elemental
• 39:46level.
• 39:47There's a problem
• 39:49with glutamate
• 39:51synaptic connectivity
• 39:52and glutamate synaptic function.
• 39:54And the genes,
• 39:56schizophrenia is an eighty percent
• 39:58heritable disorder. And a number
• 40:00of the genes that are
• 40:02implicated in schizophrenia, both rare
• 40:04and common variants,
• 40:05are involved in synaptic development,
• 40:08glutamate synaptic function,
• 40:10or glutamate synaptic elimination.
• 40:13But there's,
• 40:14another theme there,
• 40:17which has to
• 40:18do perhaps as a consequence
• 40:20of,
• 40:22of the excitatory
• 40:24deficits
• 40:25is the the interneurons
• 40:27just are dysfunctional.
• 40:29And and the interneurons
• 40:31are the tuning mechanisms,
• 40:34like the the way you
• 40:35tune the station on a
• 40:36radio to get a good
• 40:38signal.
• 40:38And if you have a
• 40:39problem
• 40:40with GABA in the brain,
• 40:42it wouldn't be surprising that
• 40:44the circuits are dysregulated,
• 40:46maybe even
• 40:47grossly disinhibited.
• 40:50So
• 40:51this brings us back to
• 40:53the ketamine story that I
• 40:54began to tell you a
• 40:55little bit earlier.
• 40:57So
• 40:58ketamine's effects may not be
• 40:59mediated by dopamine,
• 41:01but one interesting finding from
• 41:03the very early days from
• 41:05Robbie Green's lab, beta Mogadam's
• 41:07lab, Ray Dingledine's lab, and
• 41:09other people's lab lab, was
• 41:10that that if when you
• 41:12gave an NMDA receptor antagonist
• 41:15at at subanesthetic
• 41:17doses,
• 41:18you reduce the firing rate
• 41:20of GABA interneurons
• 41:23and you increased
• 41:24glutamate neuronal firing rate and
• 41:26increase the extracellular
• 41:28levels of glutamate in the
• 41:29brain.
• 41:31In other words,
• 41:32that even though ketamine
• 41:34blocks an excitatory
• 41:35receptor, the NMDA receptor,
• 41:38it a component of its
• 41:39effects
• 41:40are are
• 41:42perhaps mediated
• 41:43by disinhibiting
• 41:45cortical circuits as well.
• 41:48And so a study that
• 41:49we,
• 41:51conducted way and published way
• 41:52back in two thousand twelve,
• 41:57was we,
• 41:58James Stone,
• 41:59who's now the chair of
• 42:00psychiatry in the University of
• 42:02Sussex in England,
• 42:03gave,
• 42:04patients with,
• 42:06healthy people, excuse me, ketamine
• 42:08and measured the increase in
• 42:10cortical glutamate level with proton
• 42:12magnetic resonance spectroscopy.
• 42:15And what he found was
• 42:16that as these glutamate levels
• 42:18rose more and more and
• 42:19more,
• 42:20that you started to get
• 42:21the emergence of more severe,
• 42:25transient psychotic symptoms in the
• 42:27healthy subjects. So cortical disinhibition
• 42:30produced by ketamine
• 42:34mirroring the story that I
• 42:36told you earlier about cortical
• 42:37disinhibition
• 42:38increasing the propsychotic
• 42:40effects of amphetamine.
• 42:43Disinhibition
• 42:44seems to be a store
• 42:45a a theme in psychosis
• 42:47research.
• 42:49I'm gonna tell you another
• 42:50story now
• 42:52about cortical disinhibition
• 42:55mainly because I think it's
• 42:56cool.
• 42:57And,
• 42:58you may or may not
• 42:59think it's cool, but it
• 43:01it it will help you
• 43:02to understand about how we
• 43:04think about cortical circuits and
• 43:06cognitive function
• 43:07and why why disinhibition
• 43:09may be a problem for
• 43:11cognition as well
• 43:12as as symptoms like psychosis.
• 43:15So let's think about two
• 43:17modes
• 43:18of cortical function and say
• 43:20in prefrontal cortex, and we'll
• 43:22target a specific
• 43:23cognitive function called working memory.
• 43:26That's like the ability to
• 43:27remember
• 43:28a telephone number. You know,
• 43:30you dial the telephone number,
• 43:31you can't even remember
• 43:33what that telephone number is
• 43:34after you dialed it. It's
• 43:35like a scratch pad as
• 43:37as Patricia Goldman and Keach
• 43:39used to say.
• 43:40So one property that enables
• 43:42this kind of working memory
• 43:44is something called feed forward
• 43:46excitation.
• 43:47One neuron activates another and
• 43:49is in turn activated by
• 43:50that neuron. And so that
• 43:52activity kind of ping pongs
• 43:54or reverberates
• 43:55and main and by doing
• 43:57so, keeps information
• 43:58online.
• 44:00Another mode mode of function
• 44:02is feed forward inhibition.
• 44:05I want to remember this
• 44:06and not that. The neuron
• 44:08that's coding this is activated,
• 44:10but that doing so turns
• 44:12off another,
• 44:14neuron that's encoding
• 44:16that which you forget.
• 44:18And so let me show
• 44:20you what that looks like
• 44:21in the study that Srinivas
• 44:23Rao did when he was
• 44:24working with Patricia Goldman Rick
• 44:26Each.
• 44:27The the
• 44:29the x axis is time.
• 44:32The,
• 44:33the height of the of,
• 44:35you know, of those bars
• 44:37tells you about how many
• 44:38neurons are firing.
• 44:39And what you can see
• 44:41is that when you're trying
• 44:42to remember a particular
• 44:44location,
• 44:45that the neurons in the
• 44:46prefrontal cortex that code for
• 44:48that particular location
• 44:50stay active
• 44:52as long as you keep
• 44:53that information on mind.
• 44:55And at the same time,
• 44:57the neurons that code for
• 44:59a distractor location
• 45:01at the other
• 45:03zero to a three hundred
• 45:04and sixty degrees or hundred
• 45:06and eighty degrees this way,
• 45:07you know, the neurons that
• 45:09you're that are encoding the
• 45:10target stay active. The neurons
• 45:12that are coding the other
• 45:13direction are silenced.
• 45:15And that gives you
• 45:17precise
• 45:19information encoding in memory.
• 45:21If you take out the
• 45:22GABA neurons by giving a
• 45:23drug very similar to iomazinil,
• 45:26a GABA a,
• 45:27inverse agonist,
• 45:29You oops. You get more
• 45:30activity in the target region,
• 45:32but you also lose the
• 45:34ability
• 45:35to suppress the noise.
• 45:37So inhibition
• 45:39gives you the ability to
• 45:40tune
• 45:42neurons
• 45:43at neural activity that gives
• 45:45us precision
• 45:47in our spatial memories.
• 45:50So
• 45:51we can look at what
• 45:52ketamine does to this.
• 45:55Early,
• 45:56well,
• 45:56reasonably early on, Amy Arnston
• 45:59infused
• 46:00ketamine
• 46:01right into the brain in
• 46:03the prefrontal cortex neurons that
• 46:04are activated during the encoding
• 46:07and maintenance of working memory
• 46:08and showed that by blocking
• 46:10NMDA receptors, you really,
• 46:13at high levels, you can
• 46:14really wipe out the ability
• 46:15of those neurons
• 46:16to maintain information online.
• 46:20When we
• 46:21move this work, and this
• 46:22is work that Alan Antitrovich
• 46:25was extremely
• 46:26important in developing in collaboration
• 46:28with John Murray and others,
• 46:30Shaoxing Wang, etcetera.
• 46:33What we found is that
• 46:35when you encode
• 46:37information in working memory
• 46:40and get, you get this
• 46:41nice,
• 46:42pattern of activation
• 46:45in in blue. And if
• 46:47you give ketamine, you attenuate
• 46:48that activation
• 46:50just as MK two one
• 46:51attenuated that activation.
• 46:53But in other parts of
• 46:55the brain, like the parietal
• 46:56cortex,
• 46:58which is inhibited
• 47:00when information is being kept
• 47:02online,
• 47:03ketamine also reduces the ability
• 47:07to suppress the noise,
• 47:09to suppress to inhibit that
• 47:11part of the brain.
• 47:12And so you get this
• 47:14reduction in signal
• 47:17and
• 47:18amplification
• 47:19of noise.
• 47:20And You might say, well,
• 47:21what does that have to
• 47:22do with schizophrenia?
• 47:24The answer is schizophrenia has
• 47:26the same pattern, a reduction
• 47:28in signal, a failure to
• 47:30suppress noise.
• 47:32And John Murray
• 47:33modeled the computational steps
• 47:36needed. And in order to
• 47:38in this simple circuit model,
• 47:41you can achieve this pattern
• 47:43if you not only interrupt
• 47:45the e to e,
• 47:47excitatory neuron to excitatory neuron
• 47:49communication,
• 47:50but you also reduce the
• 47:52drive to the inhibitory neurons.
• 47:54In other words, you disinhibit
• 47:56the circuit and you allow
• 47:57the noise
• 47:59to be more fully expressed.
• 48:03He also used another
• 48:05model,
• 48:06it's called a bump integrator
• 48:08model, which give enables you
• 48:12to,
• 48:13generate
• 48:14precision in spatial locations.
• 48:17It's sometimes called on center
• 48:19off surround. You remember the
• 48:21target. You ignore the periphery.
• 48:24And and that's because
• 48:26you get
• 48:28inhibitory
• 48:28control of the neurons coding
• 48:30the peripheral stimuli,
• 48:32and you don't inhibit directly
• 48:34the and you allow the
• 48:36ones that are coding the
• 48:37center to be activated.
• 48:39What that gives you in
• 48:40this computational model is the
• 48:43ability,
• 48:44to encode if the target
• 48:46is presented here to represent
• 48:48that target very precisely with
• 48:50just a little bit of
• 48:52spatial imprecision.
• 48:53And so it's really easy
• 48:55in working memory to distinguish
• 48:58this target
• 48:59from this probe.
• 49:02When you when we modeled
• 49:04the ketamine effect, the
• 49:06reduction in inhibition,
• 49:08what we saw was a
• 49:09broadening
• 49:10of this neural representation.
• 49:12And something really funky happened,
• 49:15which is that the model
• 49:17started to recognize the
• 49:19probe distractor
• 49:21is being part of the
• 49:22memory. In other words, you
• 49:24had a contamination
• 49:25of memory
• 49:26or the in the computational
• 49:28model, the generation of even
• 49:30false memories,
• 49:31which is interesting when we
• 49:33talk about a disorder like
• 49:34schizophrenia.
• 49:35So how did this play
• 49:37out in terms of translating
• 49:39it
• 49:40from a computational model to
• 49:42behavioral
• 49:43model? And
• 49:44and Alan,
• 49:45really elegantly
• 49:47developed
• 49:48a very excellent spatial working
• 49:50memory test where we could
• 49:51look at the precision
• 49:53of information
• 49:54represented
• 49:56in working memory. And you
• 49:57can
• 49:58see that all the healthy
• 50:00subjects
• 50:01are very
• 50:03tightly clustered around the target.
• 50:05And the patients with schizophrenia
• 50:08are picking areas,
• 50:11misidentifying
• 50:12areas
• 50:13being farther and farther away
• 50:14from the target, a less
• 50:16precise
• 50:17representation. And you can see
• 50:18this is,
• 50:20affected,
• 50:20magnified
• 50:22by increasing space, temporal delay
• 50:24when you test.
• 50:26What's interesting
• 50:27is that you get the
• 50:28same effect, and this is
• 50:30a paper that's not yet
• 50:31published. And Massey is here
• 50:33today,
• 50:34who is leading this, paper,
• 50:37Massey Romati.
• 50:39And you
• 50:40see that speed ketamine is
• 50:41reducing, like schizophrenia,
• 50:43the precision
• 50:44of information encoded in spatial
• 50:47working
• 50:48memory. Further,
• 50:50when you use a different
• 50:51kind of working memory task,
• 50:53you see that you start
• 50:54to get false alarms,
• 50:56misrepresented
• 50:58representations.
• 50:59They're
• 51:00seeing a distractor stimuli
• 51:02and thinking it's also a
• 51:04target. So this idea of
• 51:07of,
• 51:09of of,
• 51:11loss of precision or reduction
• 51:13in precision
• 51:14of memory
• 51:16as
• 51:18behavioral
• 51:22representation as as a kind
• 51:23of cognitive
• 51:24impairment in schizophrenia is something
• 51:27that we haven't appreciated
• 51:28and how it triggers people
• 51:30with schizophrenia
• 51:31to generate certain kinds of
• 51:33false
• 51:34representations
• 51:35as a result, which is
• 51:36kind of interesting.
• 51:37And you can actually show
• 51:40using
• 51:40these fMRI data
• 51:42that the precision the neural
• 51:44precision of the representation
• 51:47in other words, how precisely
• 51:49neurons tune their activity to
• 51:52stimuli in various aspects of
• 51:53the visual field, that tuning
• 51:55is also,
• 51:57reduced. So you have a
• 51:58reduced neural precision of activity
• 52:01associated with reduced precision
• 52:04of mental representations.
• 52:07I would like nothing better
• 52:09to than to spend the
• 52:10next hour with you telling
• 52:12you about all the other
• 52:13ways in which,
• 52:15tuning deficits in schizophrenia could
• 52:17play out both at a
• 52:18neural and a behavioral level,
• 52:20but I will spare you
• 52:21that.
• 52:23But to to you should
• 52:24understand that what I've done
• 52:26is cleave off a tiny
• 52:28fragment of a much bigger
• 52:30story
• 52:31just so that you get
• 52:31a little bit of feel
• 52:32of why I think disinhibition
• 52:34is so important.
• 52:35So what do we do
• 52:36about it?
• 52:38And how does this how
• 52:39do we bring this story
• 52:40back to treatment?
• 52:42So
• 52:43the first
• 52:44the the first drug I
• 52:45actually tested was a drug
• 52:47called lamotrigine, which I'm not
• 52:48gonna talk about today. But
• 52:51but based on beta Mogadam's
• 52:53work, the we were very
• 52:55interested in using mGlu r
• 52:57two agonist
• 52:58to
• 52:59provide inhibition to compensate for
• 53:01the disinhibition
• 53:03of the of the,
• 53:05glutamate neurons. And mGluR two
• 53:07receptors are both pre and
• 53:09postsynaptic, but I'm gonna focus
• 53:10on their presynaptic
• 53:12function
• 53:12on glutamate nerve terminals both
• 53:15in the cortex and and
• 53:16in other regions of the
• 53:17brain.
• 53:19Beta
• 53:20showed elegantly
• 53:21that you could reduce
• 53:23the PCP in disinhibition
• 53:25of cortical circuits by giving
• 53:27an mGluR2
• 53:28agonist.
• 53:29And so
• 53:30we looked at it in
• 53:31our computational
• 53:32model. Here, you can see
• 53:34the reduction in,
• 53:36in,
• 53:37precision represented by a broadening
• 53:40of the of the tuning
• 53:42curve for a given
• 53:43model neuron in the computational
• 53:45model.
• 53:47And,
• 53:48and mGluR two agonists
• 53:50would were predicted
• 53:52to restore the precision
• 53:54of that tuning. And so
• 53:55it was really interested interesting
• 53:57that when we gave,
• 54:00when we gave
• 54:02ketamine and worsened,
• 54:04neural precision impaired working memory,
• 54:06we We could, limit that
• 54:08with,
• 54:10with mGluR2
• 54:11agonism.
• 54:12MGluR2
• 54:13agonism
• 54:14didn't turn out to work,
• 54:16but m four
• 54:18turns out to reduce glutamate
• 54:20disinhibition
• 54:21in addition to reducing the
• 54:23the dopamine effects I alluded
• 54:24to earlier. And m one
• 54:26may act particularly in the
• 54:28cortex
• 54:29to reduce disinhibition
• 54:30and and restore tuning in
• 54:32the cortex.
• 54:34I'm gonna go over this
• 54:35quickly because I realize we're
• 54:36we're,
• 54:37short on time. But here
• 54:39in Amy's work,
• 54:41she has actually measured
• 54:44the the the spatial tuning
• 54:46of working memory neurons and
• 54:47showing that zenomelang improves
• 54:50this tuning,
• 54:52measure d prime,
• 54:53as it improves working memory
• 54:56function.
• 54:57The challenge with m one
• 54:59is that and this is
• 55:01from an another
• 55:02protege of,
• 55:06of Patricia Goldman, Rakichi's laboratory
• 55:08here at Yale named Vijay
• 55:09Raghavan.
• 55:11What he showed was that
• 55:12that,
• 55:13that at a low dose,
• 55:15you do get some enhancement
• 55:16of activity. It doesn't look
• 55:18very robust here,
• 55:19But you actually suppress neural
• 55:22activity associated with working memory
• 55:24below baseline if you go
• 55:25too high.
• 55:27And that's really
• 55:29the cautionary tale, I think,
• 55:31about m one
• 55:32and CAR XT and the
• 55:34new medications.
• 55:36Does m one add anything
• 55:37to the efficacy,
• 55:39cognitive, or symptomatic efficacy of
• 55:42Kobenci?
• 55:43We don't know. And it's
• 55:45hard to tell
• 55:46because too low, m one
• 55:48isn't gonna do anything.
• 55:49At the right amount, it
• 55:51might enhance some cognitive functions.
• 55:54At too high a dose,
• 55:56it worsens
• 55:58working memory.
• 55:59And Cobenvy is a drug
• 56:01that gives you,
• 56:03m four
• 56:04and m one in a
• 56:06fixed ratio.
• 56:07And so whatever that whatever
• 56:09dose you give is gonna
• 56:11stimulate those,
• 56:14receptor classes in a fixed
• 56:15kind of way.
• 56:17And so we'll have just
• 56:18have to see
• 56:19whether m one is,
• 56:21adding anything.
• 56:23So just to close,
• 56:26we're we're in a new
• 56:28agent, schizophrenia
• 56:30work. We now have for
• 56:31the first time non dopamine
• 56:33d two receptor,
• 56:34antipsychotics.
• 56:35They are going to be
• 56:36a whole class of medications.
• 56:38We will use them probably
• 56:40for people with negative symptoms,
• 56:42for people who have problems
• 56:44with the extrapyramidal
• 56:45side effects of antipsychotic
• 56:47medications.
• 56:48Hopefully, we'll use them for
• 56:49early course patients.
• 56:51We may use them adjunctively
• 56:53to augment antipsychotic response.
• 56:55So I think that they
• 56:56will have,
• 57:01broad and important effects on
• 57:04the burden of schizophrenia,
• 57:06and it will also teach
• 57:08us something about the brain,
• 57:09about the biology of cognition,
• 57:11the biology of these symptoms.
• 57:13And we will,
• 57:16use all of the tools
• 57:18in our toolbox to try
• 57:20to understand
• 57:22not only how these drugs
• 57:23work, but how to move
• 57:24the treatment even forward from
• 57:25there. So I will stop
• 57:27there, and thank you.