Yale Psychiatry Grand Rounds: April 8, 2022

April 08, 2022

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George Heninger Lecture: "Developing Novel Therapeutics for Treatment-Resistant Depression"

Carlos Zarate, MD, Chief Experimental Therapeutics and Pathophysiology Branch, NIMH

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00:00Well. Thank you so much Jerry
00:04for the kind introduction.
00:05It's truly a pleasure and
00:07honor to give this lecture.
00:09I was there last time at Yale in 2009.
00:13I I met Doctor Henninger back then
00:15but I know of all many of the stories.
00:19Wonderful teacher, mentor,
00:23researcher, clinician.
00:26And we share a story where he
00:28sounds like his second generation
00:30psychiatrist grew up and they a
00:33mental state hospital grounds.
00:35I also second generation psychiatrist,
00:39and I grew up on Norristown
00:41State Hospital grounds that we
00:43used to play there because my
00:45father was working at Norristown,
00:47we lived on Sturgis St and I think
00:49George Curtis was there and some
00:51of the earlier trials of lithium
00:53with Smith Beecham if I recall.
00:56And we used to play with our with
00:59with patients there who had the
01:01transistor radios and they would
01:03provide moral therapy and and
01:05educate them on how to socialize.
01:08So we have that common experience.
01:13So with that in mind, I'm I'm,
01:15you know,
01:15truly delighted to to give this talk,
01:17I'm going to probably have way
01:19too many slides.
01:21And just wanted to summarize
01:24the work until this point.
01:26This is my disclosure work for the
01:29intramural research program at NIH.
01:31So today's objectives are to understand
01:34briefly the cause of TRD to become
01:37familiar with rapid actin therapeutics
01:39for TRD to understand the neurobiology
01:42of promise and therapeutics for treatment
01:44resistant depression and to really get
01:47at the pharmacology understanding how
01:50ketamine works to develop better treatments.
01:53So we do know already that TRD is associated
01:56with is a major cause of morbidity,
01:59disability and mortality,
02:01and it's defined clinically by two failure to
02:06respond to two adequate antidepressant trials
02:08in the current major depressive episode.
02:11It's made about 30 to 40% will have some
02:14form of treatment resistant depression,
02:16although the numbers are probably actually
02:18higher and depression, as you know,
02:20is associated with significant mortality.
02:23Death by suicide is about 800,000 to
02:261,000,000 per year around the world.
02:29Depression has traditionally been
02:30viewed as disturbances of mood,
02:32but we know it consists of much
02:34more than that.
02:35Disturbances,
02:36circadian rhythms,
02:37activity levels with
02:38significant impairment function,
02:40and there's considerable cost with a
02:43treatment resistant depression and the if
02:46you have treatment resistant depression,
02:48you live on average 13 years less
02:50than individuals without treatment
02:51persist depression,
02:52so really impactful illness.
02:56The the criteria for DSM we we we
02:58have DSM criteria for depression
03:00and it's useful for communicating
03:03with families and with clinicians.
03:06But we know that it does not
03:08map to neurobiology.
03:09In fact there is conservative
03:11comorbidity of 30 to 40% or even higher,
03:14and so if one is trying to understand
03:17the ideology of depression,
03:19are you really looking at
03:21depression or the comorbidity with
03:24anxiety disorders or some other?
03:26Medical conditions and So what
03:29was proposed with our DOC research
03:32domain criteria was deconstruct
03:33these illness illnesses into more
03:35simpler constructs in the way,
03:37but challenge in itself.
03:39And here we have example of an adonia
03:42motoric or activity levels in suicide,
03:45and so then what you do is obtain
03:47information at very various levels,
03:49going from behavior going through
03:51Physiology circuits all the way
03:53down to genes and then especially
03:55and then eventually you can.
03:57Link and the phenotype more closely
04:00or approximate to what's going on
04:02with the ideology of the illness
04:04with the therapeutic in this case.
04:06For example,
04:07this represents changes in anhedonia,
04:10reward processing link with improvements
04:13and depression scores with ketamine,
04:16and that would be one example of how
04:18we can develop better therapeutics.
04:20Now,
04:21the rationale is that you know depression
04:23is for developing better treatments.
04:25As we have depressions associated
04:26with the disruption to personal,
04:28social,
04:29occupational life and there's a
04:31considerable risk of suicide.
04:32Although we have standard treatments,
04:34psychosocial, pharmacological,
04:36neurostimulation,
04:36they all help many individuals oppression.
04:40We use them in combination,
04:41but still Despite that we get very
04:45low remission rates.
04:46We have about 30 to 40% of treatment
04:49resistant depression.
04:50And there's a considerable lag of
04:53onset of antidepressant effects.
04:55This cartoon or this figure depicts
04:57a major depressive episode which
05:00usually lasts about 6 to 9 months.
05:02What happens when we initiate treatment
05:04with a monoaminergic based antidepressant?
05:06Is we shift the curve of
05:08response towards the left,
05:09and that response is now at 10 to 14 weeks.
05:13Now, in my mind and many,
05:16we would agree that next
05:19generation antidepressants.
05:20That could produce rapid responses
05:23of both depression and suicide
05:25within a matter of hours,
05:27and we can develop better treatments
05:29than ketamine based on an understanding
05:32of cellular molecular targets.
05:34Now this is, yes, you know this,
05:39the path or the journey to novel
05:41therapeutics was made much
05:42easier by the work at Yale,
05:44and this is the Seminole paper by Rob Berman,
05:48John Crystal, Dennis, Charney,
05:50and others showing the rapid
05:52response within a couple of hours.
05:54And it really set the the the
05:57groundwork for future research at
05:59the intramural program this work.
06:01This is a very old slide.
06:04From a paper where we had
06:07our candidate drugs,
06:08this was our understanding of the
06:11architecture of the glutamate system,
06:13the tripartite system,
06:14and we came up over the few
06:17drugs and amantine, felbamate,
06:19riluzole early on,
06:20and I'll very briefly summarize
06:23the next steps,
06:24but that we've gone through 20 years
06:27of different drugs and some of them
06:30have promised and others did not.
06:32But this is the the study that Jerry
06:36mentioned where we tested back then.
06:38But we we believe was the NMDA receptor
06:41inhibition hypothesis of depression.
06:43That is, if you're given an MD antagonist,
06:46you produce rapid responses
06:47and the answer is yes.
06:50Here we see racemic, ketamine,
06:52the depression scores,
06:53higher number,
06:54greater depression time and minutes and days,
06:57and we see an onset within a
06:59couple of hours with racemic
07:00ketamine towards the right.
07:02We see the response rates of
07:05monomer energic antidepressants,
07:06which is about 6 to 8 weeks for 65%
07:10to achieve response taken and added
07:12present everyday for that period of time.
07:15Here you see rapid responses within
07:17a couple of hours in individuals who
07:20had failed 6 to 8 antidepressants,
07:22many had failed ECT and 50%
07:25had previous suicide attempts.
07:30So.
07:31From there we now have what could
07:34be called four major classes
07:36of of drugs that have presumed
07:39rapid antidepressant effect.
07:41We have ketamine as the prototype
07:43and the antagonist,
07:45but also has effects on new
07:47opioid Kappa and other systems.
07:49The second group is neurosteroids
07:52brexanolone sage 547.
07:53It's a gab.
07:54It's a GABA a positive electric modulator.
07:58Then we have the opioids and then
08:01serotonergic hallucinogens.
08:02The prototype is silybin.
08:04Now we're really not sure,
08:06but early preclinical work suggests
08:09that there's overlaps in some of
08:12the the the effects of these drugs,
08:14so they begin at the receptor
08:16signaling level.
08:17Different places,
08:18opioid and MDA,
08:20glutamate or serotonergic,
08:21then and then we see differences
08:23in the plasticity cascades and
08:26more downstream that was believed
08:28to happen is that they overlap at
08:31network reconfiguration increase.
08:33The Neurotrophins protein translation.
08:35Spine turnover, neurogenesis,
08:36and these different systems seem to converge,
08:40and glutamate seems to be
08:42an important component now.
08:44There have been studies with this earth with
08:46the psychedelic agents and this was where,
08:49by Robin Carhartt Harris just published
08:51recently in the New England Journal,
08:54in which you see,
08:56here is subjects randomized to silybin.
08:592 doses of citalopram and what
09:02you see here is the conclusion,
09:05at least on the quiz.
09:06Was that there was at by six weeks there
09:08was no significant difference in the end
09:11of person effects versus search ruling
09:13compass just published a larger study.
09:16Looking at, I believe it was
09:192510 milligrams and 1 milligram.
09:22And what they found were response rates of
09:26about 36% at 25 milligrams at three weeks.
09:29And then there's some cases of,
09:31you know,
09:32perhaps increased rates of suicidal
09:34ideation and so on and so forth
09:37and in in the higher dose group.
09:40But these are just preliminary.
09:42The results are not all published,
09:44but leads us to believe that
09:46this could possibly be another
09:48group of drugs to to pursue.
09:51This is very high level summary.
09:54This is the Ron Duman hypothesis of
09:57depression, the glutamatergic burst,
10:00where we block GABA NMDA receptors
10:04and GABA ergic interneurons decreased.
10:06GABA release hyperpolarization and
10:08the so called glutamate, first,
10:10intracellular signaling cascade
10:12changes induction of neural plasticity,
10:15and then spine growth in synaptogenesis.
10:18Another possibility is to go more
10:20downstream to avoid NMDA receptors,
10:22and hopefully.
10:23Avoid the psychotomimetic effects would be
10:26using inhibitors that maglore to receptors.
10:29One can look at the son of
10:31ketamine to our six rhink.
10:33I'll talk a little bit about that.
10:34They all produce the glutamate
10:37burst AMPA activation,
10:39serotonergic,
10:39psychedelics at the five HT 2A
10:42receptor and also would have many
10:44of the common downstream pathways.
10:47We do not know about the neurosteroids
10:50we do know that there's.
10:53They're positive, illustrate modulators.
10:55Some argue it could be negative
10:57allosteric modulators,
10:58but they seem to tap in and similar
11:01downstream pathways early work.
11:03Now, what is important in and,
11:05and this is that biomarkers where this
11:09inhibition disinhibition or excitation
11:12of pyramidal cells one can detect.
11:18At the preclinical and also human level,
11:20looking at gamma power within
11:22the 30 to 50 Hertz,
11:23and that is a potential cross
11:26species biomarker we are pursuing.
11:29So this is a very simple schematic in the
11:32year 2000 and this is what it looks like now.
11:35Very exciting,
11:37many different targets being pursued,
11:40some of them panned out,
11:41others not.
11:42We talked about the Gabaergic interneurons
11:45and blue are two three ketamine.
11:48Seems to have effects on many
11:51different components.
11:52The Mglur 5 has also been pursued as well.
11:56Colocalized within MDA receptors.
11:58Some have actually pursued more activators.
12:01Tax 653 is still in play.
12:05Also for neurocognition one can target
12:09the extrasynaptic site receptors
12:12to produce this a plasticity.
12:16But and then of course.
12:18There are more direct targets
12:20such as mtor agonists,
12:22MV5138. Now the largest group of drugs,
12:26of course, are the NMDA receptor antagonist,
12:28and so there are listed here.
12:30One that's quite interested as dextral
12:33methadone rail 1017 and then one can
12:37target the glycine site as a way of more
12:40fine tune in the NMDA receptor complex.
12:43None of them have panned out as of yet,
12:46and then one can pursue at the
12:48subunit in order to be so.
12:50These are just high level examples
12:52of some of the drugs in play.
12:54Now to summary the brief summary to this
12:57point is TRD is to field and at the
12:59present trials it's a clinical definition,
13:01but we have to move away to that in consider
13:05biological means of defining TRD and MDA.
13:08Receptor inhibition may not be the
13:10primary mechanism of ketamine.
13:12I know that's not all schools agree on that,
13:15but we have some evidence of that.
13:17Psychedelic drugs are being explored
13:20in large studies.
13:21We'll know soon in the
13:23glutamatergic modulates with.
13:24Diverging modulates as well seems
13:26to be a promising group of drugs.
13:28Now in terms of mechanism action,
13:31this study raised whether opioid
13:34receptors might be implicated.
13:36This is studied by Williams
13:38and Alan Schatzberg's group,
13:40which you see here is that the
13:43the ketamine subjects treated
13:45with ketamine were pretreated with
13:47either placebo or say a placebo,
13:49saline or naltrexone.
13:51What you see,
13:52which is a new opioid antagonist.
13:54What you see is a diminishing or
13:56attenuation of the antidepressant effects,
13:58but the dissociate side effects
14:01do not diminish with the use of
14:04naltrexone work by Matt Klein.
14:09They argue that it's not an effect as
14:13an opiate, but more that it affects
14:16both NMDA and opioid signaling,
14:18and so that's something to
14:20consider in future development.
14:21So we were quite intrigued with
14:24with these findings and decide to
14:26pursue this a little bit more. First,
14:29a very brief summary of racemic Academy.
14:32When administered,
14:33you have within a few minutes in
14:36mice or in humans, 24 metabolites.
14:39Over 24 potentially different drugs.
14:42Towards the right you see here the
14:44pathway of our ketamine can be metabolized
14:47to to R6RH K or esketamine to 26S H&amp;K.
14:52They do not enter convert
14:53and so these two compounds,
14:55the two or six are in the two
14:58success do have antidepressant
14:59like properties in animal models.
15:02So this work was done and collaboration
15:04is was done in a Mike Michaelides
15:07lab by Jordy Buenaventura,
15:08and we were interested in better
15:11characterizing the the pharmacology
15:13of Esketamine versus archenemy.
15:15Here we see a screening receptor
15:18enzyme profile in here.
15:20It's very tiny,
15:21all the different receptors and enzymes,
15:23and what you find is, not surprisingly,
15:25both S cademy and our ketamine.
15:29Bind PCP,
15:30But what was interesting here is we
15:33found that as ketamine at 10 micro
15:37molars was binding to muoio receptors.
15:41When you look at competitive radioligand
15:43binding essays towards the left,
15:45you have MK to one for an MDA.
15:47Receptors in orange is.
15:49That's ketamine.
15:50You see that the displacement is
15:52greater for S compared to R ketamine.
15:54We know that that S is already four
15:56times more potent than archenemy, but.
15:59Where are opioid receptors?
16:00They're they're summarized down here.
16:02New opioid receptor is greater for S,
16:05the S and antiwar compared to R,
16:07and also for the capital opioid receptor.
16:10For the Sigma,
16:11it's the flip side R in anterior,
16:13as greater effects on Sigma receptors
16:15and Sigma have been implicated in
16:18antidepressant like properties as well.
16:20The study went on to look at FDG
16:23PET imaging in awake rodents,
16:25looking at the US versus the ordinance
16:28timers and what you see with the S
16:30is that there's increase in activity
16:32and medial prefrontal cortex.
16:34Where the opioid receptors
16:36reside largely in part,
16:38and then you have the Aryan nation where
16:40what you find is a decrease activity and
16:43paraventricular in habenular regions.
16:45Keep in mind some studies suggest that
16:48there's hyperactivity of the habenula
16:51and involved in the NT reward system.
16:54When you look at autoradiography
16:56studies you see on the top is
16:59middle is esketamine you see the
17:01effects of mule period receptors.
17:03It's reversed with.
17:04Now trick with that, sorry,
17:06not naloxone,
17:07whereas there's no significant
17:09changes with our ketamine here.
17:11You can see the right basil increase
17:14with morphine increases with
17:16Esketamine reverse with naloxone.
17:19No significant changes with
17:21our the our enantiomer.
17:23The study next went on to look at the
17:27behavioral effects of these enantiomers
17:31using classical behavioral procedures.
17:34That characterize opioid
17:36in psychostimulant drugs.
17:37And here you're going to
17:38see an orange is the
17:40esketamine is the one that's elevated
17:41in all these behavioral procedures.
17:43Acute locomotion,
17:45locomotor sensitization compared to R,
17:48cross sensitization, and when you look
17:50at the condition place preference,
17:52you see it's greater with
17:53the S and then timer.
17:54No significant changes with R.
17:57What about drug sale fund ministration?
17:59You also seen the dose response.
18:01Greater increases with as compared to R.
18:05But in the extinction phase,
18:07what was distinct from opium psychostimulant
18:10drugs is that there was extinction and
18:13suggests that it's not habit forming,
18:15so they are quite.
18:17These enantiomers are quite distinct
18:18in the opioids and psychostimulants.
18:21To summarize,
18:22intervene at this to this point.
18:25Self administration was for the Esplanade ER.
18:29We see that the classical behavioral
18:32procedures separated the S from the
18:34R and in summary we see that there
18:37is a divergent in the behavioral
18:40pharmacological effects of these
18:42different enantiomers and it
18:44suggests that the abuse liability
18:46is more on the US side versus the R.
18:49Keep in mind what we're saying.
18:51What I'm saying here.
18:51Also,
18:52is that the racemic the S and the are
18:56enantiomers do share common properties,
18:59but they also may be different
19:01types of drugs and may have
19:04different therapeutic applications.
19:06So we wanna study wanted to identify
19:09more the the mechanism of ketamine.
19:13And we designed this study a few years back.
19:17It's called the ketamine's mechanism
19:19of action study the kit MOA where
19:22we where we obtain information
19:24at various levels of biology.
19:26I'm using multiscale systems
19:28biology approach and integrating
19:30a wide range of behavioral,
19:33clinical and other technologies shown here.
19:36And these where we where we
19:38where we obtain repeat measures.
19:42Now I want to summarize briefly as
19:45introducing the kid MOA study is I
19:48already mentioned that ketamine binds
19:50to the NMD? The NMDA receptor Gabbert.
19:53You can turn neurons and there's this in.
19:56Inhibition. Excitation occurs.
19:58Glutamate release occurs with ketamine.
20:02The other drug Canada drug we are
20:04looking at is Manglore 2 antagonist
20:07and we are also looking at the son of
20:11it ketamine to our six origin key.
20:14Also as a property of enhancing
20:17glutamate release without blocking NMDA.
20:19Thus,
20:19in theory you would not have
20:21the psychotomimetic effects.
20:23This study was done in Hussain Imanx's
20:27lab and what was found here is,
20:30of course,
20:30ketamine decreases the force swim test,
20:32the immobilien,
20:33the force swim test significant
20:35signifying and depression effects,
20:37but based on follow up work
20:39by beta Maugham at Yale.
20:41What was done here is we used NBQ
20:44mix and an AMP antagonist and the
20:47behavioral effects of ketamine
20:49were attenuated or blocked.
20:52So just in that.
20:53AMPA throughput is important to the
20:54antidepressant effects of ketamine,
20:56and so these different drugs
20:58they mentioned as Canada drugs do
21:00have that property in common.
21:02In addition,
21:03they also in preclinical studies,
21:05increase gamma power,
21:07which represents this
21:08neuronal synchronization.
21:09So could this be a cross species
21:12biomarker that we could use to
21:14develop drugs in here we are using
21:17several tools to examine plasticity,
21:19potentiation humans and they are gamma,
21:22power, slow, wave. Activity and TMS.
21:25In the interest of time,
21:26I might have only ability to
21:28talk about one or two of these,
21:30but this is a new study that's
21:32still underway, should be completed,
21:33hopefully in the near future,
21:35and it's called the new barrack
21:37study and I'll summarize,
21:38which is basically examining
21:40the effects of ketamine.
21:42In the scanner,
21:43subjects receiving fMRI and EEG and the same
21:47subject receiving a later time point EMG,
21:50and then repeat administration and higher
21:52low dose of ketamine with repeat biomarkers.
21:56This is the the earlier study that
21:58kit MOA study that I mentioned.
22:00Single infusion of ketamine or placebo,
22:03unmedicated depressed subjects and
22:04after two weeks crossover pretty much
22:07the design of previous ketamine studies
22:10but with longitudinal biomarkers subjects.
22:12Here now 35 have treatment resistant
22:15depression or medication free and
22:18then control subjects also received
22:20ketamine at the same time points
22:23in the same biomarkers.
22:25Subjects here were moderately depressed.
22:28They 40% had previous suicide attempts
22:30and it's a very rich data set that that
22:33I'm going to summarize a few of the studies,
22:37for example,
22:38one each subject may have had five F MRI,
22:417 T,
22:433T and polysomnography.
22:45And these are some of the publications
22:47have come out of that study.
22:49Just to show you consistent
22:51with prior studies,
22:52rapid onset within minutes lasting 11
22:55days here increases in CADS as expected.
22:59But what you see is different than
23:02standard convention and at present
23:04it's broad therapeutic effects
23:06improvements in the anxiety and edonia,
23:09anticipatory consummatory and PTSD symptoms,
23:12as well as functioning.
23:14Unexpectedly,
23:14what we found was the that healthy
23:17volunteers developed a increase in
23:20depressive symptoms temporarily,
23:22which did not correlate with the changes
23:25of of the dissociative symptoms.
23:27Subjects reported in their
23:29attention lasted to an ability to
23:31feel emotional blunting,
23:33which was not a prolonged.
23:36To summarize here,
23:37information at the circuit
23:39level here subjects received
23:41a single infusion crossover,
23:43unmedicated baseline 3T MRI in
23:45a two and a 10 days to capture
23:49the on off effects of ketamine.
23:52Specifically,
23:53looking at the default mode network settings,
23:57network and central executive network.
23:59Consistent with has been reported,
24:01we find decreases in depressive
24:03symptoms by two days and the effects
24:05start to wear off by 10 days in green.
24:08No significant changes in the the
24:11sailing condition when you link this
24:14with neuroimaging at precisely the
24:16same time points which you find here
24:19at baseline is increased difference
24:21between patients and healthy controls,
24:23and insula the salience network.
24:25Not functioning well at the peak of
24:27improvement of the present symptoms.
24:29No longer significant increases in
24:31hyperactivity of the insula and
24:33then by day 10 when the effects
24:36of ketamine start to wear off.
24:37You see a return of the activation of
24:41insulin, so this nice on off effect.
24:44Subsequently,
24:45and a hit was interested in antidote
24:48and corticostriatal circuitry
24:50into the question was that there's
24:53ketamine affect cortical
24:54striatal circuitry,
24:55and the answer is yes.
24:57Here 33 unmedicated patients,
25:0225 healthy controls,
25:03arresting state of eight minutes.
25:06And these are the seed regions,
25:08dorsal kodia, ventral stratium, ventral,
25:11rostral putamen and dorsal caudal putamen.
25:16And what you see here are the
25:20global differences in racemic,
25:22ketamine, and whole brain functional
25:25connectivity across the forest seeds.
25:27Ventral freedom with dorsal lateral
25:30dorsal cardia, ventrolateral,
25:32conflict zone, and so forth.
25:34But to summarize here you see in green,
25:37placebo, orange, ketamine you see
25:39throughout the different seeds.
25:41If you're a healthy, controlled subject,
25:43you have decreased in the hole.
25:46Brain functional connectivity.
25:47If you have treatment resistant depression,
25:50you have an increase in this connectivity.
25:53So opposite directions in at the
25:56same time points towards the bottom.
25:59You see the correlation of the
26:02seed with the connectivity
26:05changes with depression scores.
26:07There's a very nice correlation of
26:11amongst the different seeds in a trend
26:14for the anhedonia with the chaps.
26:17Information at the six to to 8 hour,
26:196 to 9 hours.
26:21After ketamine,
26:22we obtained a Meg and also at baseline
26:26and this is to get at this this
26:29interplay between excitation and ambition.
26:32What we use here is gamma power,
26:34neuronal stellations in the 30
26:37to 50 Hertz range so we can use
26:40this a cross species biomarker.
26:42So here this has been very well studied,
26:45you see.
26:46Up to 30 to 50 Hertz range,
26:49a change and early visual cortex and
26:51that has been previously reported,
26:54but Gamma also.
26:55Lations can be described in
26:57many different regions.
26:58Visual, sensory,
26:59motor cortex,
27:00auditory cortex and in some ways might
27:03represent plasticity phenomena and thus
27:05might be a useful putative biomarker
27:08to understand better understand.
27:11Ketamine gamma rhythms correlate
27:14with neuron action potentials.
27:16They are invading sensory
27:19perception information code in,
27:22especially in hippocampus,
27:23and during cognitive tasks Now what
27:27generates gamma part we don't know for sure,
27:29but some work suggests it's at the
27:33level of parvalbumin inhibitory's
27:36with the pyramidal cells excitation
27:38and what you see here are these micro
27:41circuits that have been described
27:43called the Interneuron network gamma,
27:45or the ping, when the pyramidal.
27:47Those involved.
27:47Why is this important?
27:49Well, with electrophysiological
27:50measures and five Tomic.
27:52Providing example,
27:54you can generate estimates of the
27:58excitation inhibition into formulas and
28:01then calculate the regional dynamics
28:04that are going on at this level.
28:08Now,
28:08what about at resting state?
28:10We obtained a Meg at 6 to 9
28:12hours after ketamine at the peak
28:14when antidepressant fix happened
28:16in the dissociative side.
28:18Effects of have diminished towards the top.
28:22You see the press subjects, the bottom.
28:24You see healthy controls and you
28:26see increases in gamma power in the
28:29default mode network in the triple network,
28:31specifically towards the right you see,
28:33for example,
28:34in green,
28:35the right insula increases with ketamine.
28:38That approaches the healthy control
28:40subjects baseline,
28:41so it suggests normalization here and
28:44also within the central executive network,
28:47so ketamine is doing a lot of things.
28:49But here our interest is in a triple network.
28:53And, importantly, that the baseline
28:55gamma power seems to moderate the end
28:58of the prison effects of ketamine.
29:00The lower the gamma power, the better.
29:03The antidepressant effects of ketamine.
29:04The higher suggest no response
29:07or even worsening subjects with
29:10who are treated with Academy.
29:12Now we now move into a stimulus
29:16induced gamma power changes.
29:18As I mentioned earlier,
29:20this was earlier work where one does a
29:25sensory task which you use in nomadic
29:27device to stimulate the sensory cortex
29:29you could see here the plastic changes
29:32that occur and this is referred to
29:34as stimulus induced gamma power.
29:36So you select within the
29:3830 to 50 Hertz range.
29:39In an earlier study we looked at 21.
29:42Dedicated subjects and.
29:44What you find here at baseline,
29:47no difference between responders and
29:50non responders. But post ketamine.
29:52You see that stimulus induced gamma
29:55power significantly increases compared to
29:58baseline suggestion plasticity phenomena.
30:00Now we went on to replicate this in
30:03the control study I mentioned earlier
30:05and on the bottom what you see here
30:08are the responders using the same task
30:11increase in stimulus induced gamma power.
30:13Non responders, no changes,
30:15healthy control changes,
30:17no changes in gamma power,
30:19suggesting specificity.
30:21Towards the right you see the peak,
30:23gamma, ketamine,
30:24placebo differences at the
30:26peak of the antidepressants.
30:28Effects of ketamine,
30:29which is at 24 hours in a very
30:32nice correlation.
30:33So here we have some evidence
30:36of a replication at our lab.
30:39Now we're interested in more
30:40in the dynamic measures,
30:42and so, in this experiment,
30:4418 unmedicated subjects were
30:45treated with ketamine or saline.
30:48The usual crossover design.
30:50We use the same task.
30:52Source localized gamma power using
30:55the pneumatic device you can see
30:58the changes in sensory cortex.
31:00Towards the bottom you can see
31:02Erps on the top control with
31:05baseline ketamine placebo.
31:07These are for one individual.
31:09In the bottom is for a patient.
31:12So what we used here is dynamic
31:15causal modeling to get at this
31:18excitation inhibition model,
31:20and it's a way of estimating and
31:23making inferences about coupling
31:25within different brain regions.
31:27But the difference here is that you
31:30make a change in the experimental
31:32context and the perturbation,
31:34and then you measure that change.
31:37So here you can see control,
31:39you do a perturbation in this case.
31:42Sensory task I mentioned and you measure
31:45that change and you obtain what we
31:48call changes in effective connectivity.
31:50And keep in mind this was done
31:53at 6 to 9 hours of post ketamine.
31:56Going back at the micro circuit level,
31:59what's interesting is you can then
32:02generate based on the the the,
32:06the physiochemical properties of the
32:09channel biophysical models of AMPA.
32:13NMDA and GABA function.
32:14I'm not going to talk about that now,
32:17but you can generate estimates
32:19of how much excitation you have,
32:22how much inhibition you have,
32:23and this is what we refer to
32:26as regional dynamics.
32:27And also you can measure
32:29these dynamic changes in what
32:31we call a A a geometric plane called
32:34the trace determinant plane to to get
32:37a sense of where do subjects move in
32:39terms of their inhibition and excitation,
32:41and how is that related to the
32:43antidepressant? Effects of ketamine.
32:45And so this is work by Eric Fagerholm at.
32:49And UK and what you see here
32:52towards the top left are patients.
32:54Bottom you see controls and you see
32:57this southwest orientation of this
32:59plane where you have the changes
33:01in modulus scores and the changes
33:03in this trace determinant plane.
33:05This is associated with response.
33:07If you plug in the numbers.
33:09Unfortunately this is at work,
33:11but you have excitation excitation
33:14and ambition.
33:15You come up with this these estimates
33:17and what you would find here.
33:19This movie doesn't work.
33:20Is that as you go through the different
33:23subjects at the different times,
33:25you find a change in excitation
33:27ambition and subjects move to the
33:29southwest direction that's associated
33:31more with antidepressant response.
33:33This now is available online if you want
33:35to plug in your numbers and see if it works.
33:37We're looking for replication.
33:40Right, let's see, oh, sorry,
33:41now the next is I talked to you about
33:45the six to 9 hours of gamma power, right?
33:48That probably represents
33:49non NMDA AMPA throughput,
33:52cortical excitability.
33:53So, how early do the change
33:55of gamma power happen?
33:57We know glutamate changes
33:58may happen in 15 minutes,
34:00and so this is a question
34:01we've been looking at.
34:02The new Barrett and the New Barrett study
34:04where we are doing measures of fMRI,
34:07EEG, and the scanner,
34:08and also MG.
34:09And looking at these different tools.
34:11So here using the same task as,
34:13this is a different sample.
34:16Some matters sensory cortex.
34:18We see changes in gamma power
34:20almost immediately with ketamine
34:23during the infusion, 6 to 9 hours.
34:25It seems to increase.
34:27Again, this is very preliminary.
34:28We have to look at the data.
34:29No significant changes in the
34:31placebo or saline condition.
34:33So so just that there's something
34:35going on very early on,
34:37maybe consistent with the glutamate burst.
34:39Now earlier work to get it plasticity
34:43potentiation because if we believe
34:45that there's a glutamate burst and
34:48activation suggest plasticity is that
34:51we we did a study and published it
34:53probably some time back where Julia
34:57Tononi what he noticed was that if
34:59you do a new visual motor task here,
35:03the person sitting on the computer,
35:04something not previously learned
35:05what you find at night is increasing
35:08the slow wave activity precisely.
35:10In the area of the motor changes
35:12and suggest that they're probably
35:14plasticity changes going on,
35:16so in collaboration with them we did.
35:18We wondered whether ketamine
35:20might be involved in this.
35:21Could this be a putative marker
35:24of synaptic potentiation?
35:25The simple cartoon here is that in
35:29responders you would have in AMP
35:32insertions and haptic potentiation.
35:35In Nonresponders there would be no insertion,
35:37no seductive potentiation,
35:39so.
35:39Early work in rodents suggests that
35:42when you give ketamine injections
35:44and medial prefrontal cortex,
35:46you find increases in synaptic strength.
35:49And you also find increase
35:51in slow wave sleep.
35:52That's delta between 0 and 40 Hertz.
35:56So we wondered whether
35:58this also occurs in humans,
36:00and so in a previous publication,
36:03this looks at changes in slow wave
36:05sleep in the first cycle you see
36:09significant increases with ketamine and
36:11red compared to the baseline and blue.
36:15And so we have in in the earlier work
36:18what we found as a relationship that
36:22responders to ketamine seem to have.
36:25Increases in slow activity
36:27compared to non responders.
36:29It's taken us a while but we've been
36:31able to to look at and subsequently
36:33replicate this just recently.
36:35So Torres are right.
36:36If you look at healthy control subjects,
36:38what you see this is SWA slow wave activity.
36:41What we know is that through the three
36:43cycles it tends to diminish over time.
36:46This is normal,
36:47but somehow if you look
36:49towards the depressed subjects,
36:51what you find is that this is disrupted.
36:53They don't have this normal
36:54pattern as healthy.
36:55Control subjects and in the next
36:57slide which you see is here,
36:58they're grouped up in green is
37:00healthy volunteers and the red or
37:02orange is the treatment resistant
37:04depression and we see you know
37:06that what I just showed you,
37:07the decrease in the healthy
37:09control and it's disrupted in in
37:12the depressed subjects towards the
37:14right after ketamine there this is
37:17no longer significantly different,
37:19suggesting there's normalization,
37:21so this pattern, it seems to normalize the.
37:25And put it back into play.
37:28Now if you look at in the next
37:30slide is the responders versus non
37:33responders towards the top left
37:36which you see here is that there's
37:39a general increase in the responders
37:41at 230 minutes.
37:43This is statistically significant
37:44whereas the non responders it seems
37:47to be flat or actually diminishes.
37:49So suggested that synaptic could
37:52potentially be a synaptic appellative.
37:55Markets and naptip potentiation.
37:58Now I'm going to skip this in the
38:00interest of time to get into the
38:02last piece of the story is that
38:04what would we noticed early on
38:06on the research unit was in.
38:08This is clinical observation is the
38:10half Life Academy is a few hours
38:13dissociate side effects last 40
38:15minutes after the infusion and but
38:17you you have this ongoing and at the
38:19present response and it fades off
38:21by the end of one week to two weeks.
38:23We really talked about so early
38:26on we wondered whether.
38:28The Academy Is actually a pro drug
38:31and what maybe some of the mentalists
38:33might be active and at a present,
38:34and so in collaboration with many
38:37tagula at University of Maryland.
38:39Craig Thomas at Ncats and Pat Morris
38:43and and ruined model and others.
38:47Urban Weiner but was identified
38:50is that we found these metabolites
38:53lasting 3 to 7 days and we said,
38:56wow,
38:56that's around the same time as the
38:58duration and personal effects,
39:00and we said, wow, this is interesting.
39:02So we went.
39:02What are these H&amp;K metabolites and
39:04we
39:05found disappointingly that they
39:06were inactive when we say inactive,
39:09that was it was inactive for
39:11what pain and anesthesia,
39:12but we decided to pursue that.
39:14And it's a series of studies
39:16that led to a candid drug.
39:18Who are sick Sarah and Kate?
39:19The two successive is also an antidepressant,
39:22but we pursued this for other reasons.
39:25To briefly summarize,
39:27you give racemic ketamine.
39:29And what you find is in rodents
39:32high levels of ketamine,
39:33and then the metabolite 2 or 6 origin K.
39:37Through a process where you strengthen
39:40carbon 6, you produce D2 ketamine.
39:42You die, deteriorate, deteriorate,
39:44ketamine when you do so.
39:46Towards the right,
39:48you effectively reduce or eliminate
39:51the metabolism of Academy.
39:53So in essence,
39:54now you have D2 ketamine and
39:56if you look at the bottom left,
39:58this is the competitive binding assay.
40:01MK 801 for an MDA receptors,
40:03you see an overlap between D2
40:05ketamine and racemic ketamine.
40:07Would return retains its
40:10pharmacological properties,
40:11and when you test D2 ketamine it
40:14no longer has the sustained effects
40:17of of of of racemic Academy towards
40:20the right we take our Canada drug
40:23which is 2R6RH K and effective.
40:26We see it in Nice dose relationship
40:28with different doses and both
40:30acute and depressive effects,
40:32and sustained antidepressant
40:33antidepressant effects of H&amp;K.
40:37To to the top shows row shows that our
40:42candidate drug does not displace MK to one,
40:45so suggesting it would not have an MD
40:48and then an MDA inhibitory properties.
40:51There is no changes in prepulse
40:53inhibition and no increases in
40:55lever presses suggested there's no
40:57abuse potential towards the middle.
40:59I'm not going to go in just to summarize,
41:02when you give and be QX and
41:04AMP and antagonist you block.
41:06Canada person effects not only have ketamine,
41:09but of our Canada drug.
41:11H&amp;K suggests an AMP activation
41:13throughput is important.
41:14Towards the bottom we see
41:17increases in gamma power.
41:18Towards the left you see the the changes in
41:22gamma with racemic ketamine also with 2R6R18
41:25Care Canada drug and towards the right.
41:28We see the figure showing
41:30increases in green of gamma power,
41:33but it's blocked with pretreatment with NBQX,
41:36so again,
41:38suggesting a potential biomarker.
41:40To summarize this part of the story
41:42of a cartoon you give ketamine,
41:45racemic, ketamine within minutes.
41:47You have two dozen metabolites.
41:51Some of them we could argue
41:52involved in side effects addiction,
41:54others in the rapid antidepressant effects.
41:56How do we separate them?
41:58We do so by process called we do
42:00turate carbon 6 strength and carbon.
42:03You effectively reduce or eliminate
42:05or block the metabolism we take
42:08our create new newly created drug
42:10which is the same as racemic
42:12ketamine without the metabolism.
42:14The two ketamine when we do so
42:16it doesn't have the sustained and
42:18the present effects of ketamine,
42:20but still has a side effects.
42:21But side effects in addiction,
42:23addictive properties,
42:24we take our candidate drug to our six R.
42:27We inject it in rodents.
42:29It's not an MD antagonist.
42:31At physiological concentrations
42:33it doesn't have abuse potential,
42:36it activates AMPA.
42:38And it says we,
42:39in essence we separate the wheat
42:41from the chaff.
42:41I think I have about a few minutes left.
42:45We've done some deconvolution
42:49studies deconstructed.
42:51To our six Origin key,
42:52this is unpublished work and
42:54what we can summarize here using
42:56the competitive binding.
42:57Radio login assays is that
43:00it doesn't inhibit an NDA.
43:02It doesn't have effects on new opioid
43:05receptors or capital opioid receptors.
43:08When we do FDG PET imaging of rodents
43:12treated with saline or 2R6RH and K,
43:15you see that it does increase insulin
43:18activity, metabolic activity,
43:20and insular nucleus. Combines.
43:21Towards the bottom right or
43:23matrices you see the changes with
43:26Esketamine to our six RHK has a
43:28different pattern than as ketamine,
43:30suggesting that these are different drugs.
43:34To summarize what I'm going to move on to,
43:37the last couple slides.
43:41Ketamine has different potential
43:43theories on its mechanism.
43:45Blocking extrasynaptic receptors,
43:47synaptic NMDA receptors,
43:49Gabaergic and NMDA receptors,
43:51and Gabaergic interneurons with the
43:54glutamate burst or metabolism through
43:57liver producing hydroxy nor ketamine
43:59and increase in release of glutamate.
44:02AMPA activation downstream changes
44:05I already showed you the changes in
44:08gamma power in preclinical studies.
44:11In a recent study we looked
44:14at the combined 2
44:15success to our six R 18K.
44:18In in our subjects and we find
44:20increases in gamma power.
44:21So suggesting that the changes also might
44:25be relevant to developing the drug.
44:28Just recently completed is a
44:30study where we looked at CSF,
44:32plasma and CSF for 28 hours,
44:35paid in in healthy volunteers
44:38who received ketamine.
44:39They had the MG and what you find here.
44:43There's a bottom left.
44:44You could see the changes in 2R6,
44:46R and two success.
44:48We see greater the area under the
44:50curve for CSF is significantly,
44:53however, to our six R compared to
44:55two as success and also in plasma.
44:57Here are the ratios though.
44:59The figure on the right shows
45:02you that over time,
45:04the changes in metabolite
45:05levels we can see here the 230.
45:08A minute time point we see that
45:11they start to diverge where
45:13two or six are increases,
45:152 success decreases in both CSF and plasma,
45:19whereas it remains relatively flat
45:21for it nor ketamine, and for ketamine.
45:24It drops very dramatically,
45:26suggesting well what's really
45:28the the key player here.
45:29I'm not going to show you
45:31the Meg data very recently,
45:33a paper published by Vasiliy
45:36Kotula and Mitul Mehta's lab.
45:39Looked at reward processing and
45:41remitted depressed subjects and gave
45:44ketamine in the point of this is
45:46so you can study reward processing
45:49changes without being influenced by
45:51improvement in depressive symptoms.
45:53A pretty clever study and this is
45:56the monetary incentive delay task.
45:59We have.
46:00Low winds,
46:01high winds and neutral winds and
46:03what you find here is the greater the
46:05activity and ventral tegmental area.
46:08The the the.
46:09With a positive relationship with the
46:11metabolites who are six RH and Kane,
46:13their study but not with the
46:16other metabolite,
46:16so suggesting that there's a
46:19potential other biomarker that could
46:21be used and suggest that perhaps
46:23to our six or eight and K might
46:25be a promising candidate drug.
46:27And I might have time for nothing else,
46:30right? I think so.
46:31Just to show you this was this
46:34is the last data. That we have.
46:38It's under review where we look.
46:40We did a metabolomic analysis of
46:42the plasma and CSF in our healthy
46:45volunteers who received the 40
46:47minute infusion in a parallel
46:49study by tag looking at a plasma
46:52hippocampus and and looking at
46:55either ketamine or to our 614K.
46:58What you find in red are the
47:01humans and in yellow are the mice.
47:04But to summarize why ketamine
47:06has brought therapeutic effects?
47:07Don't know,
47:08but you can see here by metabolomic
47:11changes that there are changes.
47:13In many systems, nitric oxide signaling,
47:16mitochondria,
47:17oxidative capacity and tour
47:19cholesterol metabolism.
47:20Bile acids,
47:22which also have effects as
47:24neurotransmitters and inflammation,
47:26changes in kind learning pathway.
47:29Nam,
47:29and then ceramide pathways of will as well.
47:34So these are potentially could
47:35explain in part why it has
47:38brought therapeutic effects.
47:39And to summarize,
47:40this is some of the ongoing work we're doing.
47:44We're testing and do our to our antagonist.
47:47We, with Taisho, we have finished
47:49phase one and the study is going
47:51on right now in our research unit.
47:53It's an indoor 2-3 antagonist.
47:56We have completed single ascending
47:59dose of of H&amp;K and started we'll
48:02start multiple ascending dose and
48:04hopefully in the first quarter of 2023.
48:07Tested and TRD. To summarize.
48:10We obtain information at many levels.
48:12Molecular cellular.
48:13We collaborate with our
48:16extramural colleagues,
48:17give them information they give
48:19us information and which helps
48:21us carry the signs forward.
48:22We obtain information at
48:24the circuit system level,
48:25obtain multimodal measures and
48:27the longitude of fashion to
48:29better understand treatment,
48:31and then hopefully the goal
48:33would be to obtain a biologically
48:35enriched subgroups so that we can
48:38have a better understanding of
48:40mechanism and pathophysiology.
48:41So I'd like to stop there and
48:43thank you for your attention.