Yale Psychiatry Grand Rounds: April 8, 2022
April 08, 2022Information
George Heninger Lecture: "Developing Novel Therapeutics for Treatment-Resistant Depression"
Carlos Zarate, MD, Chief Experimental Therapeutics and Pathophysiology Branch, NIMH
ID7662
To CiteDCA Citation Guide
- 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&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&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&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&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&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.