Child Study Center Grand Rounds 05.04.21

June 08, 2021

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Rapid-acting Treatments for Pediatric Depression and Suicidality: Where are We Now?

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00:00Welcome everyone to today's grand rounds.
00:02The the one thing that I want to say
00:06is about next week's grand rounds.
00:08Then I'll pass it to Michael to say
00:11about today's very special grand rounds.
00:13So next week I have to say that
00:17it's a particularly meaningful and
00:18special grand rounds to me personally,
00:21and to many people in the
00:23child Study Center in that
00:25we're going to have this second
00:27annual Max Ritvo Alan Slifka.
00:30Grand Rounds and you'll
00:31learn more about them
00:33as the announcement comes out,
00:35but suffice it to say that I think
00:37this will be the first time that we're
00:40going to have something like a play.
00:42I don't know exactly
00:44what you're going to call
00:46it, but it's going to be a very
00:48unique type of grand rounds.
00:51Our presenters Susie rule.
00:52Sarah Ruhl is a acclaimed playwright.
00:55She is on faculty at the
00:57Yell School of Drama, which,
00:59as you probably know,
01:01is the top drama school, probably in
01:04the world. She's
01:05an acclaimed writer, an author,
01:07and she will speak about
01:09something that is very,
01:11very personally meaningful,
01:12as I say. Two, she personally
01:15to me personally to Laura Cardona.
01:17Too many of us who were touched in
01:20many ways by Max Ritvo, so I really
01:23look forward to all of us joining
01:26you then. So
01:27that's next week. But today,
01:29the main event we were fighting
01:31each other Michael Block, and
01:33I say no.
01:34I introduce her. Now you introduce
01:36her now, I mean, but eventually
01:39Michael one and I think that it's only
01:42right because Jennie did the wonderful
01:44presentation introduction of Michael
01:45when he gave his grand rounds sometime.
01:48Last year and now Michael Block
01:52Mentor Supreme will introduce
01:54the great Jenny Dwyer Jenny.
01:56We're delighted you're here, Michael.
01:59Take it away. Pam Unmuted,
02:02I guess I it's really my pleasure to
02:05introduce Jenny Dwyer and I I guess
02:07I'll go with the beginning of the
02:10official boring introduction because
02:12just to prove I can do it and then
02:15I'll talk a little bit about her
02:17as a person and really highlighting
02:20the great thing she's done here.
02:23So Jennifer Dwyer is currently an
02:25assistant professor at the Child
02:27Study Center and in the Department of
02:29Radiology and Biomedical Imaging at Yale.
02:32She completed her MD and pH D in
02:35pharmacology at the University of California,
02:38Irvine,
02:38better known as the Anteaters,
02:41where she studied the development of
02:43the dopamine system in adolescence.
02:45We were then lucky enough to recruit
02:48her to the Sony Integrated program in
02:51Child and adult psychiatry research
02:53where she transitioned to have to
02:56conduct more clinically oriented
02:58research that's really informed
03:00by her expertise in neuroscience.
03:02Former pH D at Irvine she's going to
03:05present on novel research examining
03:07cada mean as a novel therapeutic
03:09for treatment refractory depression
03:12in adolescents,
03:13and she's just starting till
03:15lunch in our one grand looking,
03:18entitled reducing adolescent suicide risk,
03:20safety and efficacy,
03:22and connect home phenotypes of
03:24intravenous Academy that focus on
03:27testing the effects of repeated dose.
03:29Cada mean as a novel therapeutic in
03:32adolescent treatment refractory depression.
03:34And using neuroimaging to explore
03:36predictors of treatment response,
03:37and I guess,
03:38the stuff that I'd really like
03:40to say about her personally,
03:42that I think doesn't come through
03:44in the Tri introduction,
03:45is just that she's really the epitome of
03:48a gifted clinic physician scientist that
03:50we try to develop in the soulmate program.
03:53That if you were gonna have
03:55a mascot for the program,
03:57he would be the mascot.
03:58Either that or a Unicorn and then
04:01hopefully people will get that reference.
04:03And and then I guess the other thing to say.
04:06Is a Andres in introduced
04:08me as a mentor supreme,
04:11but I think when we're talking
04:13about this research,
04:14I think it's really important
04:17to recognize that really.
04:18The idea for this study and this
04:22line of research really came out
04:25of Doctor Dwyer's experience as
04:28a as a resident on the CN Ru.
04:31Seeing the I guess the efficacy is
04:33of cada mean and esketamine in the
04:36studies that were conducted there
04:38and adults and really having the
04:40vision to recognize the important
04:43clinical need in adolescence and
04:44what a great sort of research
04:46program that would develop.
04:48And I think one of my main roles of
04:51of as a mentor was recognizing her
04:54brilliance and and being smart enough
04:56to encourage her on her pursuits
04:59and Ann and really take up what's.
05:02Turned into a wonderful research
05:04program and the other thing
05:05I've learned about doing talks with her
05:08and introducing her is that the more
05:10time I give her to talk, the better,
05:12so I'm delighted to introduce her.
05:15Oh, thank you, Michael.
05:18That ladies and gentlemen,
05:20is as warm and fuzzy as Michael
05:22Bloch gets, and it's wonderful.
05:27So I really appreciate you guys inviting me.
05:30Today I realized as Michael was talking
05:32and naming some of my projects,
05:34I realized that I sort of
05:37like a long title I guess.
05:39So here's one more I'm talking about
05:41rapid acting treatments for pediatric,
05:43pediatric depression and suicidality and
05:45really thinking about where are we now?
05:48So let's get going.
05:51In terms of disclosures,
05:52I don't have any relevant
05:54conflicts of interest to disclose.
05:56I've got my research support listed here.
05:59And then I thought I'd just outline
06:01what we're going to talk about today,
06:03so I'm going to talk a little bit
06:06about depression and suicide.
06:07And adolescence.
06:08I'm going to talk about
06:10interventional psychiatry,
06:10treatment modalities for
06:11depression in adults.
06:12I am going to focus mostly on CADA mean,
06:15but I think since this is such a new,
06:18rapidly evolving subfield within
06:19psychiatry that it was a good idea
06:21just to give a little overview of
06:24what interventional psychiatry
06:25even is referring to,
06:26but will focus on cada mean.
06:28And then we'll talk.
06:29A little bit about pediatric cada mean,
06:31so the work that I've done here
06:33with Michael and Jerry Santa
06:34Cora are single dose randomized
06:36controlled trial in adolescent
06:37treatment resistant depression.
06:38And then I'm going to spend a fair
06:40amount of the time talking about
06:42the gaps in our understanding and
06:44as you'll see there are many.
06:46There is a lot of work to do
06:48and enough work to go around,
06:50so I'm excited to sort of talk that
06:53through with the broader community.
06:55And then I'll talk about a couple
06:57ways that my lab is starting
06:58to try to address those gaps,
07:00and then hopefully there will be a
07:03little bit of time for discussion.
07:05So I'm interested in adolescence.
07:07I've been interested in adolescents
07:09since my PhD work and adolescence.
07:12As this group knows,
07:14is a critical developmental period,
07:16it's the period of transition
07:18between childhood and adulthood,
07:20so conservatively defined between
07:2212 and 18 years in humans.
07:25And there is a unique set of
07:27behaviors that are conserved
07:28actually across mammalian species,
07:31and these are familiar features
07:32to folks that have adolescents
07:35at home or work with adolescents,
07:37and they include increased risk,
07:39taking increased novelty seeking,
07:41and spending more time with their peers.
07:45But adolescence is also a critical time
07:47in terms of psychiatric disorders.
07:50So it's a time of onset for things
07:53like substance use disorders,
07:55and several of the neuro psychiatric
07:58disorders that we see that persist
08:01into adulthood.
08:02And I think that these unique.
08:05Both the strengths and vulnerabilities
08:07are really mediated by changes in
08:10the structural, neurochemical,
08:11and functional organization of the
08:13brain during this time period.
08:17So now I'll focus a little
08:19more on adolescent depression.
08:21And as all of you know,
08:22this is a really significant health problem.
08:25I think that is kind of come out and
08:28smacked us in the face with the pandemic,
08:30even though it was already a
08:32significant problem pre COVID
08:34nearly one in five adolescents will
08:36experience major depressive disorder.
08:38Suicide is now the second leading
08:41cause of death in this age group.
08:44The tabs trial showed us that 40% of
08:47adolescents with depression failed
08:49to respond to initial treatment with
08:51selective serotonin reuptake inhibitors.
08:54And then that data was built upon in
08:57the tortilla trial and that showed us
09:00that of that SSRI resistant population,
09:03nearly half don't receive relief
09:05after either switching medications
09:07or adding psychotherapy.
09:09And so that tells me that we need
09:12better options for treatment
09:13resistant adolescent depression
09:15and the official guidelines really
09:18sort of end at the TORIA trial,
09:20which finished over a decade
09:22ago at this point.
09:23And so we really need clinical trials
09:27and more more data for this group.
09:30I also wanted to bring up some
09:32sobering facts about suicide on this.
09:34Data is actually a little dated now.
09:36I think this was 2017 data from
09:38the CDC and this was looking
09:41at high schoolers in the US.
09:43She reported that 17% had reported
09:46that they considered attempting
09:48suicide in the last year.
09:5014% had a suicide plan in the prior year,
09:548% reported an actual suicide
09:56attempt in some shape,
09:58way or form,
10:00and then 3% made a suicide attempt
10:04that required medical attention.
10:06The actual death rate at this time for
10:09suicide was 13 per 100,000 among adolescents,
10:12and that comes out to about 5500 per year.
10:15I'm somebody that really needs
10:17tangible things to hang big numbers on,
10:20and so I think about Hampton High School,
10:23which is just down the street from us.
10:26Many of our patients attend school here.
10:28This is 1100 students,
10:30and so this number is the equivalent
10:33of losing 5 handed high schools
10:35to suicide every year.
10:37And it's just a totally unacceptable
10:39fact to me. We have so much work to do.
10:44And we can do better.
10:48So I'll just describe a case to
10:50kind of get your minds in the right
10:53place as we start to think about.
10:55Some of the data here,
10:56so I'm going to talk about Emma.
10:58She was a 13 year old girl
11:00who was depressed with me,
11:01diagnosed with depression
11:02when she was 12 years old.
11:04She tried multiple antidepressant
11:06medications and talk therapies,
11:07but she remained very depressed.
11:09She had four psychiatric hospitilization's
11:11over a single year and one of
11:14them was for over four months.
11:16Her depression and suicidal
11:17ideations and she had made plans
11:20to hang herself with the belts and
11:22her parents were understandably
11:23terrified and were unable to leave her
11:26supervised for any amount of time.
11:29And none of the hospitalizations,
11:31medicines or therapies seem to be working,
11:34and everybody, doctors included,
11:35were starting to feel pretty desperate.
11:37And I bet a lot of you all know
11:42patients or cases like this.
11:44So now I'm going to shift towards
11:47treatment and talk about this idea
11:49of interventional psychiatry.
11:51If we were all in the same room,
11:53I would ask people to raise their hands
11:55on how many people have heard this term.
11:57This was a term that was actually
11:59coined in 2014 by Nolan Williams
12:01and Mark George down at M USC.
12:03And I think part of it was sort of
12:07medical specialty envy a little bit.
12:10So cardiology has interventional
12:12cardiologists,
12:12radiology has interventional radiologists,
12:14and so they coined this term
12:17interventional psychiatry.
12:18And what that encompass is really
12:21neuro modulation techniques,
12:22and I'll show some of those.
12:24Some are old,
12:25some are new and then also
12:27encompassing these rapid acting
12:29pharmacotherapies that typically are
12:31not administered by the oral route,
12:34so require some sort of procedural equipment.
12:37So examples include
12:39electroconvulsive therapy or ECT,
12:40which as you know is an older method,
12:44but can be a very effective treatment.
12:47Repetitive transcranial magnetic stimulation,
12:49which is a newer treatment that was
12:52sort of inspired by ECT in some ways,
12:55but is an outpatient procedure.
12:58Deep brain stimulation or vagus
13:01nerve stimulation would also
13:03count under this definition.
13:06And then when we're thinking about
13:08the rapid acting pharmaco therapies,
13:10we're talking about things like
13:12Esketamine or cada mean infusion therapy.
13:14And that's kind of what I'll
13:17focus my talk on.
13:18And then I'll also add this new medication,
13:21brexanolone,
13:22which was recently FDA approved
13:24to treat postpartum depression.
13:25So these are the types of treatments that
13:27fall under interventional psychiatry
13:29and multiple institutions are now having
13:32interventional psychiatry fellowships.
13:33Not every place has everything on this list.
13:37But it's sort of a growing
13:40subfield within psychiatry.
13:42So I'm going to focus my talk on cada mean.
13:46So Cada mean is a medication
13:48that's traditionally categorized
13:49as a dissociative anesthetic.
13:51It's a non competitive MDA or
13:53glutamate receptor antagonist.
13:54You might remember it from anesthesia,
13:57rotations in medical school,
13:58so this is given at higher doses
14:01and anesthesia.
14:02So like one all the way up to four and
14:05a half milligrams per kilogram
14:08given quickly over a minute.
14:10And that contrasts with
14:12its use in psychiatry,
14:13which is at much slower and slower doses.
14:16So the prototypical dose being
14:18.5 milligrams per kilogram,
14:19over 40 minutes.
14:22When we think about cada means acute
14:25side effects and safety profile,
14:27these are some of the things
14:29we think about again.
14:30Sort of harkening back to our anesthesia
14:33experience so there can be transient
14:35increases in heart rate and blood pressure.
14:38Those are dose dependent.
14:39It can increase the respiratory rate,
14:41but it really high doses.
14:43It could cause respiratory depression.
14:45It can cause nausha dizziness or diplopia.
14:49And then it can also generate
14:52emergent anxiety dysphoria,
14:54dissociation like symptoms,
14:55sensory distortions,
14:56or derealization,
14:57so has kind of a unique side effect profile.
15:05But the reason that people
15:06are excited about cada mean,
15:08and we're willing to tolerate some of
15:10these side effects was this finding,
15:12you know, way back,
15:13almost 20 years ago now,
15:15showing that ketamin rapidly improves
15:17depressive symptoms in adults.
15:18So this was one of the original
15:20papers coming out of Yale,
15:22and you can see that there is a reduction
15:25in depressive symptoms at 240 minutes,
15:2724 hours, 48 hours, and 72 hours.
15:30So when you think about that compared
15:32to traditional antidepressants,
15:33which can take up to 8 weeks to
15:36improve depressive symptoms,
15:37this is a really big deal.
15:40The inset is looking at the side
15:43effect timecourse just to show
15:44that the side effects dissipate
15:46and have a separate time course
15:48compared to the efficacy time course.
15:54People are also excited about cada
15:56mean in adults from this data from Sam
16:00Wilkinson here at Yale showing that Cada
16:03mean is also anti suicidal in adults.
16:06So even after controlling for its
16:08antidepressant effects, there is a
16:11distinct rapid anti suicide effect.
16:14And I think this is a really big
16:17deal for child psychiatrist as we
16:19think about the black box warning.
16:22So this idea that an antidepressant
16:24could simultaneously treat depression
16:26but also increase the risk for
16:28suicidal thinking and so a compound
16:30that's both antidepressant and
16:32distinctly anti suicidal would be a
16:34very helpful thing in our population.
16:36And I don't think it's always a given
16:39that these two effects travel together.
16:44I'll also mention Esketamine,
16:46so thinking back to chemistry class,
16:48cada mean itself as a receiving mixture.
16:51It has a left hand,
16:53the S an A right hand the R and
16:56esketamine is just the left sided
16:59enantiomer of this of cada mean.
17:01This was the compound that was developed
17:04by Janssen and recently FDA approved.
17:06The reason that they chose S cada mean
17:09is that it has a higher affinity for the
17:13MDA receptor compared to our CADA mean.
17:16And they thought that there might
17:19be some potential for a lower
17:21amount of dissociative effects
17:23compared to Racine Academy.
17:25This was a big deal when this
17:28was FDA approved in adults about
17:31probably more than a year ago.
17:33At this point,
17:34it's marketed as bravado and the FDA
17:37indication is for treatment resistant
17:39depression in adults when taken
17:41alongside a standard antidepressant,
17:44and this is an intranasal
17:46delivery versus an Ivy infusion,
17:48and the pediatric studies
17:51for Esketamine are ongoing.
17:53I'll talk briefly about mechanism of action,
17:56so people were sort of excited
17:58about cada mean because we've had
18:00a long line of SSRI's and SNR eyes,
18:02and really focusing on the
18:04serotonin system and its cousins,
18:06and so cademy really has this
18:08distinct mechanism of action.
18:10Highlight to show this cartoon just
18:12to remind people that Cyantific
18:14cartoons are getting a little much.
18:16It's hard to really follow this.
18:18I think for a clinical audience.
18:21And So what are the what are
18:23the main points in this figure?
18:25You know,
18:26the idea is that in depression we
18:28have reduced synaptic plasticity.
18:30You can see this kind of sad
18:32little dendritic spine.
18:33It doesn't have a lot of media,
18:36and if it doesn't have enough
18:38glutamate or receptors and then
18:40you see this nice healthy synapse
18:42on the right hand side.
18:44And the idea is that cada mean
18:47inhibits these inhibitory interneurons
18:49and sort of disinhibits.
18:52The system causes this burst of
18:55glutamate and growth factors and
18:58really promotes synaptic plasticity.
19:01I've summarized that here because
19:03I think it's sort of easier to
19:05think about it in words.
19:07So the bottom line is that cada mean
19:10enhances glutamatergic signaling.
19:11It promotes synaptic plasticity.
19:13The key sites of action are the
19:15prefrontal cortex and the hippocampus.
19:18There's two main hypotheses.
19:19One is the one that I just described in
19:23the busy cartoon that NMD a receptors
19:27on inhibitory interneurons are blocked,
19:30and that basically facilitates
19:32glutamate signaling.
19:33And then there's a second,
19:35although not mutually exclusive,
19:37hypothesis that some of cada
19:39means metabolites so hydroxy,
19:41nor cada mean may sort of bypass
19:44an MDA receptors in tirolian,
19:47directly activate AMPA receptors.
19:49Either way,
19:50both hypotheses are that you
19:52know these compounds are pro,
19:54glutamatergic and pro synaptic plasticity,
19:56inducing.
19:57If you're interested in more stuff like this,
20:00put in a plug for the national
20:03Neuroscience Curriculum initiative
20:05where we have a 10 minute video that
20:08sort of goes into this in a little
20:11more depth called sad synapses.
20:13So check that out.
20:16So thinking about cada mean and
20:18pediatric pharmacology, what are the
20:20things that we need to keep in mind?
20:23So I said at the beginning that
20:24the brain is going through rapid
20:27development during this time,
20:28and the prefrontal cortex is a
20:30place of big action in that regard.
20:33So the very place that we think
20:35Cada mean is working is undergoing
20:37all of these big changes.
20:39So there's synaptic pruning
20:40of glutamatergic synapses.
20:41There's a changing relative
20:43profile of these interneurons,
20:44the very places that were
20:46hypothesising that cada mean.
20:47Working and even changes in the
20:50receptor subunit composition
20:51across some of these key receptors.
20:54So I think it's not a given in this case,
20:57or really in many cases that just
20:59because something works in adults that
21:01it will work in pediatric populations,
21:02or that it even will work in the same way.
21:07But what we do know is that
21:09we've got some preclinical data,
21:11and that suggests that CADA mean
21:13can reverse depressive phenotypes
21:14in adolescent rats.
21:15So we've got that going for us.
21:17And then we also know that Keta mean
21:19has been used safely as an acute
21:21anesthetic in Pediatrics for over 50 years,
21:24so we have enough data to go on.
21:26I think that this is at least
21:28a reasonable thing to test,
21:30and so that's what we did.
21:31This was part of the work I did
21:33is a soulmate resident here.
21:35We call this the kids study.
21:37A cada mean in adolescent depression
21:39study and we asked a simple question
21:41is a single dose of cada mean safe
21:43and effective in adolescents with
21:45treatment resistant depression?
21:47And this was funded by a pilot
21:49award here at Child Study Center
21:51as well as the grant from 8 cap
21:54in the Flash for Research Fund.
21:56In this paper,
21:57just came out in a JP a couple of weeks ago,
22:01so I'll tell you about the folks
22:03that we included in this study,
22:04so we were looking for adolescents.
22:07We were looking for depressed adolescents.
22:10We were looking for significantly
22:12depressed adolescents.
22:13So children's depression rating
22:15scale score of over 40.
22:18We were looking for treatment resistance
22:20and here we define that as having
22:22failed to achieve remission with at
22:24least one prior antidepressant trial.
22:26Although as you'll see,
22:27our sample for the most part had tried many,
22:30many medications by the time they came to us.
22:34And this was a cada mean in
22:37addition to kind of study.
22:38So folks needed to stay stable on
22:40their psychiatric medications for
22:42the month prior to enrollment,
22:43and were allowed to continue
22:45with ongoing psychotherapy.
22:46So it's really cada mean in addition to.
22:49The regimen you're on that's not working.
22:52The folks that we did not
22:54include in this study,
22:56so this was an outpatient study.
22:58We excluded folks that were
23:00inpatient at the time or had
23:02active suicidal ideations that
23:04will require an inpatient stay.
23:06So while the depression criteria
23:08were relatively stringent,
23:09we did not allow for a
23:11large degree of suicidal
23:13ideations in this initial study,
23:15we excluded folks that had a history
23:17of psychotic disorder or manic episode
23:20history of substance dependence
23:22or positive urine toxicology.
23:24Pregnancy or anyone that was unable
23:27to provide written informed consent.
23:29I'll talk a minute about the controls and
23:32blinding so placebo rates are pretty high
23:34in depression trials across the board,
23:36but they're really high in
23:38pediatric depression trials,
23:39and we can talk about the reasons for that.
23:42If you all are interested.
23:44But we thought it was really
23:46important to have a control and
23:48to have a rigorous control,
23:50and so we used midazolam as
23:52what's called an active control.
23:54So mad as Liam is a benzodiazepine,
23:56it has some acute effects that
23:58we think might mimic some of the
24:01acute effects that Ketamin has,
24:03and it has a similar pharmacokinetic profile.
24:07Additional measures we took to
24:08protect the blind included having
24:10separate safety and efficacy raters,
24:12so folks that were there for the
24:15infusion or separate from the folks
24:17that performed the efficacy rating.
24:19So all the ratings were down at
24:22the Child Study Center and all
24:24of the infusions here were done
24:26at the hospital research unit.
24:28This is the study design,
24:30so this was a randomized,
24:32medazzaland controlled crossover trial.
24:34It was a four week study so infusion
24:38days were on day zero and a 14 on those
24:42days are participants got an infusion
24:44of either khetani Norma Dazzle lamb.
24:47These are sort of standard weight based
24:50doses from the adult literature so CATA
24:52beta .5 milligrams per kilogram spread
24:55over 40 minutes and medazzaland at 0.04.
24:585 milligrams per kilogram also
25:01spread over 40 minutes every hour.
25:03We looked at side effect rating scales.
25:06We also collected some blood samples
25:09from these patients to look at cademy
25:12metabolites and potential biomarkers.
25:15And then,
25:15as you might imagine,
25:17we talked with these participants
25:18quite a lot,
25:19so we did reading scales on all of
25:22the day's noted here in a subset.
25:24We actually did a little bit of neuroimaging,
25:27and also did some implicit association tests.
25:32So this is the participant flow through
25:34this study we assessed 26 participants.
25:3719 of those consented for the trial,
25:3917 went on to receive the first infusion,
25:42so one withdrew prior to the first infusion
25:45due to an undisclosed medical condition.
25:47And then one panicked prior
25:49to the first infusion,
25:51right as we were about to hit start
25:53on the pump and decided that he
25:57would prefer not to participate.
25:59Out of those, 1711 were randomized by
26:01the Investigational Drug Service to
26:03receive the sequence of midazolam,
26:05and then cada mean,
26:07and then six were randomized to
26:09the opposite sequence.
26:10Cada mean, and then the dazzle AM.
26:14All of the folks on the left completed
26:16the second infusion and then on the
26:18right you can see one person improved
26:20after they received that first infusion,
26:23an withdrew from the study to go
26:25receive cada mean in the community,
26:27and after we broke the blind,
26:29it was determined that participant
26:31did indeed receive cada mean.
26:34This is describing our sample,
26:35so this was a heavily female
26:37sample which I think is consistent
26:39with the gender difference.
26:41In depressione incidents we
26:42see that emerges after puberty,
26:44the average age was 15 1/2,
26:46but if you check out the histogram
26:48you can see that we had pretty
26:51good representation across the
26:52age range that we were targeting.
26:55About half were local to Connecticut.
26:57If you look at the baseline scores
26:59for folks that use these measures,
27:01these are high scores.
27:03So a CDRS with an average around 63.
27:06That's pretty similar to the baseline
27:09characteristics in the tortilla study,
27:11and a mattress of 33.
27:14The average age of depression
27:16onset was 13 years and the average
27:19duration was 21 months.
27:20So you can see that these are folks that
27:23had been depressed for a really long time.
27:27This is a really chronic,
27:28relatively severe sample and the
27:30average number of failed antidepressant
27:32trials was hovering around 3:00.
27:34So even though our entry criteria
27:36required only one,
27:37most people had failed several.
27:40In further characterizing the sample,
27:42about half had a history of suicide
27:45attempt little more than half had a
27:47history of non suicidal self injury.
27:49And as I mentioned,
27:51this was a study where folks stayed
27:53on their medications and got cada
27:55mean in addition to so this list
27:58is characterizing what kinds
27:59of medicine's people were on.
28:01So unsurprisingly,
28:02many people on an SSRI or SNR I.
28:06About percent with
28:07antipsychotic augmentation.
28:08One person on lithium and then
28:10a couple other mood stabilizer
28:12medications in there as well,
28:15and two participants that were
28:17not taking any medication.
28:20OK, so let's look at the data.
28:23Our primary outcome was the mattress.
28:2524 hours after infusion,
28:27comparing participants after they
28:29received medazzaland versus cada mean.
28:31And as you can see,
28:33depression scores went down significantly
28:35following cada mean treatment.
28:37This is an effect size of about .75,
28:40which is pretty similar to the adult
28:44literature for midazolam controlled studies.
28:47If we dig in a little deeper,
28:49so past this primary outcome,
28:51we can look at the percentage of responders.
28:54So here on the right you can see
28:56that there were eight participants
28:58that responded to cada mean only,
29:00in addition to five responders who had a
29:03response to both cada mean and mad as lamb.
29:06In these studies,
29:07you're considered a responder.
29:09If your depression score.
29:12Decreases by more than 50%
29:14within the first three days,
29:16so you can see significantly
29:18more Academy in responders
29:19than medazzaland responders.
29:21This is another way of looking
29:23at the same data,
29:24so again eight people that
29:26responded to cada mean that did
29:28not respond to midazolam versus
29:30one person that responded to
29:32midazolam and not cada mean.
29:37This is the time course,
29:39so this is looking at the Madras score
29:42overtime all the way out to 14 days,
29:44which is the longest time period that
29:47we examined in this short term efficacy
29:50study and you can see that again you
29:52can see the day one finding here,
29:55but you can see that the groups remain
29:58separated all the way out to 14 days,
30:00so encouraging finding after
30:02a single infusion.
30:05I added some unpublished data here about
30:08a subset of our participants that took
30:11an implicit association task I have
30:13in the title of the talk were talking
30:16about anti suicide responses as well and
30:18as you saw in the inclusion criteria,
30:21we really didn't have a lot
30:24of explicit suicidality,
30:25but we did use implicit association
30:27task to look at both depression
30:30and suicide associated cognitions.
30:32For those of you that aren't
30:34familiar with the 80,
30:35this is a test that measures reaction
30:37time to assess how quickly a
30:40participant can sort words or pictures
30:42that flash in front of the screen.
30:44So pairing words together.
30:45So in this example,
30:47pairing me with happy versus not me and sad,
30:50and the sorting speed reflects how
30:51tightly we associate two concepts.
30:53So if we already really tightly linked
30:55the idea of ourselves with being happy,
30:58people are,
30:59reaction time would be quicker for that
31:01than the association of self with sad.
31:04So quicker sorting indicates
31:06a stronger association.
31:08And this is just a subset again
31:11of our participants.
31:12So sort of a preliminary data kind of figure.
31:15We did four different high 80s and you
31:18can see that there is really little
31:20difference for the self harm and anxiety.
31:23I 80s but we see some nice separation
31:26that just escapes conventional
31:27significance here for both the Depression
31:30I-80 but also for the suicide I-80,
31:32which is sort of an intriguing finding.
31:35You know,
31:36given our questions at the top of the talk.
31:41I'll talk briefly about side effects.
31:43It's nice when things work,
31:45but we want to know that they
31:47work at a tolerable Safeway,
31:49so this is looking at intra
31:51infusion dissociative side effects.
31:52We use the cads.
31:55This figure, an alternate title
31:57would be medazzaland is not a great
31:59control for cada mean studies
32:01'cause you can see that there's a
32:04significant difference between cada
32:05mean and midazolam in terms of side
32:08effects associated side effects.
32:09I think the other important pieces
32:12that these dissipate really quickly
32:14and no one had any persistent
32:17dissociative reactions or states.
32:19I think this is kind of an
32:21interesting slide because it lists
32:22the most prominent intra infusion
32:24side effects for both compounds,
32:26so these are individual items that
32:28are pulled out of the cads scale,
32:30and then I highlighted ones that were
32:33similar between cada mean and midazolam.
32:35So you can see feeling like you're
32:37spaced out is something that people
32:39experience on both feeling disconnected
32:41from your body is also something
32:43that it's experienced in both,
32:45although more in the Academy in Group.
32:47But then you can see some things
32:49are distinctly cada mean.
32:51So, feeling like you're in a dream,
32:53most participants have that experience,
32:55and that's really not an experience
32:57that people have made as a lamb.
33:02This is looking at intra
33:04infusion hemodynamic changes,
33:05so if you remember back at the
33:07beginning we know that ketamin can
33:09raise blood pressure and heart rate.
33:12So we see what we expect here.
33:14So this is looking at blood pressures,
33:17minutes, post infusion so you can
33:19see there's a significant increase in
33:21blood pressure in the CADA mean group,
33:23but that returns to normal.
33:25We see a similar finding here
33:27with heart rate for participants
33:29out of our 17 had blood pressure
33:31that met criteria for stage two
33:34hypertension which is 140 / 90.
33:36But none persisted past the
33:38end of the infusion,
33:40an none exceeded 150 / 95 or values
33:43that would get us very concerned.
33:47I'm talking about pharmacokinetics.
33:48I think I'm going to skip this slide
33:51just in the interest of time and just go
33:54right to the single dose conclusions.
33:56So the conclusions from this study
33:58where the CADA mean was well
34:00tolerated in this small sample.
34:05Really, that cada mean significantly
34:07improved depression symptoms at one
34:10day post infusion as measured by
34:12mattress and adolescents with TRD.
34:14We really didn't have information to share
34:16here about explicit suicidal thinking,
34:18as that was really a rule out in this study.
34:23So I gave you a teaser with the IAT,
34:26but really there needs to be a separate
34:28study that's looking at suicidal thinking.
34:30So this preliminary data suggests
34:32that cada mean may be safe and
34:35effective in the short term.
34:36But as we followed some of these participants
34:39informally after the trial was over,
34:41most people relapsed and that
34:43is consistent with what we see
34:45in adults that the effects of a
34:48single dose are really ephemeral.
34:50So the big conclusion is that
34:52more research is needed.
34:53You know this is exciting that we
34:55have a positive finding in this study,
34:57but I think the real conclusion is
34:59that we need more data as the gaps
35:01in our knowledge are considerable,
35:03and so that's what I'm going to
35:05spend the time talking about.
35:06Now I'm going to talk about four different
35:09areas that sort of keep me up at night
35:11in terms of gaps in understanding and
35:13then maybe in the question period.
35:15Folks have other ideas about important
35:17areas that we should be thinking about,
35:19but I think the first one is
35:21really extending Caribbeans.
35:22Antidepressant efficacy and one way to
35:24do that is to think about repeat dosing,
35:27so this is a paper from an adult
35:30sample back in 2016.
35:32This is showing that twice weekly dosing
35:35over three weeks yields remissions
35:37that last an average of three weeks,
35:40so a better response after getting 6
35:43infusions versus getting a single infusion.
35:46The caveat is that the range of
35:49durability was really variable,
35:50so some folks relapsed in six days some.
35:55Folks made it longer than three months.
35:58And the individual factors that
36:00paration are not well understood.
36:03We have a little bit of experience
36:05with repeat dosing.
36:07This is from a case report that we
36:10published in Jacob back in 2017.
36:13This was an individual case,
36:15a 16 year old boy with a history of ADHD,
36:19depression and Crohn's disease.
36:21Three prior serious suicide attempts,
36:23multiple failed treatments considered, ECT.
36:25But ended up going with Academy in trial.
36:29Like many of you folks have seen
36:32this data before,
36:33but this is looking at
36:35his individual mattress.
36:36So depression and SSI,
36:37so suicidal ideations scores and
36:39the arrows are showing the cada
36:41mean infusions that he received
36:43in this acute series.
36:45You can see reduction in these
36:47symptoms with the first infusion,
36:49but a further and more significant reduction
36:52following with a repeat Series A lot
36:54of times folks will say, well, what's this?
36:57This blip in the middle?
37:00Was the day that his insurance company
37:03denied the potential plan and I think
37:06everybody's Madras scores might have
37:08gone up that day and I think it's
37:11a good point to remember is that
37:13these are treatments that do not
37:15immunize you against disappointment
37:17with disappointing things happen,
37:18but this was a patient that got
37:22substantially better on a repeat.
37:24Don't say paradigm.
37:25What gives us pause?
37:27Why don't we just give repeat
37:30dosing to everybody man?
37:31So I'll tell you about the things
37:34that give us pause about that.
37:37And these are data that come from
37:40studies in humans of people that have
37:43used lots of cada mean recreationally.
37:46Or have ketamine use disorder and
37:49we see neurocognitive effects,
37:50so memory problems,
37:52attention problems and then also urological.
37:54Problems,
37:55so there is bladder damage and
37:57this sort of persistent cystitis
38:00that people present with.
38:02So those are concerning and then
38:05animal studies also give us pause,
38:07particularly in thinking about
38:09developmental populations.
38:10So animal studies that use chronic
38:12dosing at young animals show damage
38:14to areas like the developing
38:16hippocampus and prefrontal cortex.
38:18Those are important areas,
38:19and so things like cell death and
38:22white matter changes and their real
38:24issue is that the toxicity threshold of
38:27repeat cada mean exposure is not known.
38:30So we know that there is a dose that's safe.
38:34This is given anesthesia all the
38:36time and people you know don't
38:39really think twice about it.
38:40But we know there's a dose out there
38:43that's too much and there's not a great
38:46understanding in Pediatrics or in adults.
38:48Really, what that dose threshold is.
38:51So that's one piece,
38:53a second related gap.
38:54In understanding that I think about
38:56a lot is what do you do after an
38:59acute cada mean treatment series?
39:01So if we do kind of a similar paradigm to
39:04what we saw in the case report for infusions,
39:07or six infusions over a couple of weeks,
39:10what's next?
39:11What's the game plan?
39:12And so one route that people have taken
39:15is to continue cada mean in some way,
39:18so maintenance infusions,
39:19although the idea of how many an at what?
39:22Intervals those things are really
39:25not worked out very well yet at all.
39:29So a second strategy,
39:30and one that I'm sort of more partial to is,
39:34can we harness the period of Wellness
39:37and people that respond to cada
39:40mean by using more traditional
39:42psychiatric treatment approaches?
39:44I bring back another busy cartoon just
39:47to remind you that there is this idea
39:50that cada mean enhances synaptic plasticity.
39:53Synaptic plasticity is very important
39:55for things like learning and so folks
39:58have started to ask is there this?
40:00Is there a period of ketamin induced
40:03enhanced synaptic plasticity that
40:05would make things like psychotherapy
40:07more impactful and so there's
40:09a number of studies in adults,
40:11including one here at Yale
40:13with my colleague Sam.
40:15Trying to give intensive
40:17psychotherapy during the period
40:19of acute ketamine treatment,
40:21so CBT in his case.
40:25But there are a number of other groups
40:27out there that are looking at different
40:30types of psychotherapeutic modalities,
40:32so I think this is a really interesting
40:34and important area to be thinking about.
40:40The third gap that keeps me up at night.
40:42You can tell I don't get a lot of sleep
40:45and it's not just 'cause I have a newborn.
40:48I like this cartoon,
40:49says the tortoise and the hare is
40:51actually a fable about small sample sizes.
40:54And he's reading and says
40:55after 19 additional trials.
40:56Of course the results were
40:58shown to be anomalous.
41:00And so, even though I'm really
41:02encouraged that we have this
41:04positive trial that just came out,
41:06we really need larger sample sizes.
41:08If you look at the history
41:10of clinical trials,
41:11there are many stories of exciting
41:13trials with ends of 10 or 15 or 20
41:16that do not pan out in the larger term.
41:19And so we really need a concerted effort
41:23across institutions with federal funding.
41:25To try to do the rigorous studies
41:28that are needed so one question
41:30and then a second question,
41:32I think that's related is
41:34what about suicidality?
41:36Again, this was not really something
41:38that we addressed in our first trial,
41:41but it's something that's very
41:43much on our minds.
41:44So what about suicidality?
41:47And then a fourth gap in our
41:49understanding is cademy, and for whom?
41:51And this this gap has a lot of pieces to it,
41:55so you could take it a lot
41:57of different places. One is.
41:59Disorders right so in the mean ha.
42:06He presses the promised
42:07data for anxiety disorders.
42:09It has promising data for PTSD
42:11and I think you know other folks
42:14are investigating a number of
42:16other different DSM diagnosis,
42:18and I think you know I feel a
42:21few different ways about that.
42:23You know at first I thought, OK.
42:26What is this a panacea?
42:28Cada mean for everyday mean?
42:31But then when you look at the list
42:34of disorders that are up there,
42:36you know SSR eyes are the first line
42:39treatment for all four of those disorders,
42:42so it would not be outside of our
42:45history that single medication or
42:47type of medication is effective
42:49for multiple disorders,
42:50and I think that's relevant
42:52to in child psychiatry work.
42:54Comorbidity is so very common,
42:56but thinking about whether
42:58cada mean is useful in some of
43:00these other disorders as a.
43:02Totally open question.
43:05Another question about Kennedy firm is
43:08whether there are clinical features
43:10or predisposing factors that would
43:12make someone a better candidate.
43:14So a number of these have been
43:16explored in adult psychiatry.
43:18So anxious depression for awhile was
43:21sort of the hot topic for a particularly.
43:25Good Academy in case.
43:27Anhedonia or loss of pleasure
43:29is another symptom.
43:31That cada mean seems to be good at treating,
43:34and this can be a really sticky,
43:37debilitating symptom that doesn't
43:39get great coverage with SSRI's.
43:41And then a study came out.
43:43Actually quite recently that showed
43:44the adults that had a history of
43:46childhood trauma actually seemed
43:48to do better with cada mean,
43:49and I think that you know,
43:51is an interesting overlap with.
43:54A potential PTSD implication.
43:59Question of how do we separate?
44:04Today
44:07uh?
44:10Cedar wood. Out. Who would respond and
44:16who would not respond to cada mean?
44:18And I think this really gets at the
44:20of a personalized medicine goal.
44:23I think many of us,
44:24especially you know when you're seeing
44:26people that have tried many treatments,
44:28this is a very fresh.
44:31Things right, try something.
44:32It doesn't work.
44:33We try a new thing.
44:35We wait another eight weeks and we
44:38try something again and there is
44:40just so much last time you know,
44:42I think we see that in adult psychiatry,
44:45but it is really acute in child
44:47and adolescent psychiatry.
44:48Developmental time is precious.
44:51In this sort of empiric exercise of
44:53just trying things and they work or
44:55they don't work without any real.
44:57Predictive data or strategy.
45:01I think we you know patients failed.
45:07So personalizing a goal?
45:13I did this summer.
45:15Out I'm interested to hear gaps
45:17are on your to remind you how to
45:21extend the antidepressant efficacy.
45:23While the risks of repeat
45:25dosing or not fully known.
45:30The reason whether we can partner cada mean
45:33with more traditional psychiatric approaches.
45:36Does Academy have antidepressant and anti
45:38suicidal properties in pediatric populations?
45:40We need bigger studies and we need them now.
45:45And then personalized medicine approaches.
45:46So who are the best candidates for cada mean?
45:49And can we predict treatment
45:51response is ahead of time?
45:53And so I will spend my last five
45:56minutes talking about some of the
45:58work that is doing to try to get.
46:00The questions and so I'm going to talk
46:03about some repeat dosing clinical trials
46:06that we have getting ready to go.
46:09So there's two studies,
46:10so one is called the sad kid study.
46:14This is an acronym that took
46:16many weeks to develop.
46:18The severe adolescent depression,
46:19cada mean intermediate duration study.
46:21This was a mentor toward that.
46:24Starting with the Klingons tied
46:27third Generation Foundation when
46:28I was in my last year of the solar
46:31program and was bolstered by an
46:338 cap Junior Investigator award.
46:35It's mentored by Jerry and Michael.
46:38And then a second study which
46:40I'm really excited about.
46:41So this is the recent are one that I
46:44received were calling us the read study,
46:47reducing adolescent suicidality.
46:48And then I can't have a title that
46:51doesn't have some long extra subtitle,
46:53safety, efficacy,
46:54and connectome phenotypes of Ivy, Cada mean.
46:56And I'm talking about these two together
46:59because they have similar designs.
47:01I really like this design 'cause I think
47:03it balances the rigor of a parallel
47:06design trial with sort of a patient.
47:08Friendly option,
47:09so I'll tell you about these together,
47:12so both of these studies are
47:15two phase trials.
47:16So in the first phase people are randomized
47:19to receive several doses of either
47:22repeat CADA mean or repeat medazzaland AM.
47:25After that period there is an
47:28open phase of several months.
47:30The people that received cada
47:32mean just go straight through.
47:34They received standard
47:35depression treatment weekly,
47:37mood assessments and monthly
47:39cognitive and mood batteries.
47:41And then the part that I really like.
47:43Like if I were thinking about
47:44enrolling in a trial like this,
47:46my worry would be, hey,
47:47you know I'm very symptomatic.
47:49I've tried a lot of things.
47:50What if I get placebo and I don't get
47:53better like what do I do with that?
47:55And so I think.
47:58That that as a lamb if they do not.
48:04Improvement are then offered the
48:06opportunity to receive the CADA mean
48:09paradigm in the open phase and then we
48:13follow everyone over that period of months.
48:16The differences between the
48:18studies are sort of shown here,
48:21so in the sad kids, we're looking at
48:24pediatric treatment resistant oppression.
48:26The paradigm is 6 inches and there is
48:28an allowance for a couple additional
48:31symptom triggered maintenance
48:33infusions and then the primary outcome
48:36for the top study is depression.
48:38And that contrasts with the NIH study,
48:41where the population is not
48:44only pediatric TRD,
48:45but also folks that have been
48:47struggling with suicidal ideations.
48:49So they have to have both treatment
48:52resistant depression and significant
48:54suicidal thinking or action in the
48:57four months prior to enrollment.
49:00This paradigm is using four infusions and
49:03our primary outcome is suicidal thinking.
49:06So we hope that most of the people that
49:09come across our way that are appropriate
49:11for this kind of treatment would fit
49:14into one of these two clinical trials.
49:17And then the last piece which
49:20I'm really excited about.
49:21You might have noticed this tiny brain
49:24just appeared under the enroll in
49:26randomized and we've worked to try to
49:28get at that prediction personalized
49:31medicine piece by incorporating
49:33neuroimaging strategically into
49:34these clinical trials.
49:35So this is a collaboration
49:37with Todd Constable,
49:39who's here at Yale in the Department
49:42of Radiology and Biomedical Imaging.
49:44And so we're interested in functional
49:47connectome response predictors.
49:48So what does that actually mean?
49:51So Todd's lab has developed this.
49:55This algorithm called connectome based
49:57predictive modeling and what that
49:59means is that you go in a magnet.
50:01You do some resting state stuff where
50:04you just rest you do a series of
50:07tasks which are listed below and the
50:09tasks are designed to try to sort
50:11of stretch your brain across all
50:13of these different neurocognitive
50:15domains and by getting like a full
50:17picture of how your brain is working
50:19across all these domains,
50:21you get this highly individual connectome
50:23fingerprint and then you try to see if that.
50:26Highly individual fingerprint is
50:28associated with treatment response.
50:29The scan time is under an hour,
50:33so we think it's feasible and why
50:35I'm excited about this is Todd's
50:38group is showed that you can predict
50:41with this approach.
50:43Symptoms of interest,
50:44so things like inattention in
50:46ADHD sample or autism scores,
50:48and a mixed sample of ADHD and autism.
50:52Sarah Yep,
50:53slab here has used this for
50:56treatment outcomes.
50:57So she had a great paper and a JP
50:59that showed that they could predict
51:02success in cocaine use disorder
51:04using this kind of approach,
51:06but there really has not been any pediatric
51:09work trying to predict treatment response.
51:12With neuroimaging in a clinical trial design.
51:15So I'm super excited about
51:17this and hope it can move us.
51:19Maybe one step,
51:21one inch closer on the personalized
51:24medicine front.
51:25I'm also excited because
51:26I think that NIH is really
51:28starting to prioritize
51:30rapid acting interventions,
51:31so this was a highlight that they
51:34published recently about the RFA
51:36that my new grant is through,
51:38so there were eight studies awarded
51:41and four of them are for youth,
51:44so I'm really encouraged by that.
51:46So mine is there at the top.
51:49There's a group at Cleveland Clinic that's
51:51also doing a pediatric cada mean study.
51:55In a group at you T.
51:57Southwestern,
51:57and then I also highlighting I I sort
51:59of listed all these interventional
52:02techniques including our TMS,
52:03but I didn't really talk about our TMS.
52:06The rest of this talk,
52:08but there's also an R TMS study that's
52:11trying to use that technique to reduce
52:14suicidal ideations in adolescence.
52:16So I threw a lot of things that you during
52:20this hour and I guess to summarize them,
52:23I view the current status
52:25as cautious optimism, but.
52:28I think the unknown risk profile
52:31of the repeated exposure component
52:33makes the risk benefit analysis
52:36really complicated to do.
52:38So the things that I think about you
52:40know folks don't fit neatly within
52:43a clinical trial is that patients
52:45should be truly treatment resistant,
52:48so carefully confirming
52:49their past treatment trials.
52:51There needs to be informed
52:53consent about the risks,
52:54the benefits,
52:55and just our overall state of understanding.
52:58There needs to be direct supervision by
53:01physicians that have adequate training
53:03and having a solid follow up plan.
53:06And then the last sort of plug for
53:09the work that our group is doing.
53:12Is this work that we started doing
53:13during COVID as more pediatric
53:15patients and families seek
53:17interventional psychiatric services?
53:18What kind of availability attitudes or
53:20practice parameters do they encounter?
53:22And so we really wanted to hear
53:24from providers in the Community
53:26about what do you know about these?
53:29Do you know how to refer someone to these?
53:32Do use these yourself and so you are
53:35exactly the people that we wanted to talk to.
53:38If you snap a photo of this QR code,
53:42it will take you to a survey
53:44that just asks about attitudes,
53:47availability and practice parameters of
53:49these types of treatment modalities.
53:51'cause I think we know that finding
53:53any kind of mental health treatment
53:56can be really daunting,
53:58particularly in the current climate.
54:00With COVID stretching people very thin,
54:03so looking for specialized care of
54:05this nature, I think is even more.
54:08Tricky,
54:09and so we'd like to see what kind
54:12of things our patients are facing.
54:15So I'm going to stop there and just
54:18say thank you so to our patients
54:21and their families to current
54:23and past lab members.
54:25To my mentors Michael and Jerry,
54:27who have just been supportive,
54:30an amazing both during my
54:32residency and fellowship,
54:33but perhaps even more importantly,
54:35during the junior faculty period,
54:37which is tricky.
54:39So I really appreciate their work.
54:42In their help,
54:43and then of course,
54:44the folks that are funding the
54:46work down on the bottom left and
54:48I would be happy to take any
54:49questions or chat in the couple of minutes
54:52that we have remaining. Thank you.
54:59So thank you very much for the
55:01excellent talk. I'm actually
55:03not gonna ask a question 'cause
55:05I got stuff in chat. My
55:07chat has been blown up with questions
55:10for you, so I guess I was gonna start
55:13off by just calling on a future solemate
55:15Max Rowlison who had a question for
55:18you and Christiana Mills is on deck.
55:23Hey Jenny, thanks so much.
55:25Really exciting work and
55:27very impressive results.
55:31My question, many adolescents with
55:32treatment resistant depression kind of, as
55:35you alluded to, have Co
55:36occurring psychiatric disorders,
55:37in particular anxiety in OC
55:39D come to
55:40mind and how
55:41do you think about integrating cada
55:43mean and depression treatment when
55:45there also are these Co occurring
55:47psychiatric disorders that are likely
55:49contributing to the presentation?
55:54Yeah, I think comorbidity is a really
55:58important question and we actually are
56:01seeing this OC D depression comorbid
56:04phenotype relatively frequently
56:06in the clinical work we're doing
56:09through the pediatric TRD clinic.
56:13So I I think including those tricky
56:16cases in clinical trials is important.
56:18Oh, everyone's frozen on my screen,
56:20which is maybe not a good sign.
56:25But there's some data that cada mean can
56:28be helpful for OCD symptoms. Be that
56:31they would get relief in both domains.
56:37Thank you.
56:42Christiana, Europe north.
56:43Thank you. So thank you so much for
56:46that presentation was really interesting.
56:48I was curious if in your newer studies
56:51it's going to be possible to collect
56:54some information about trauma in the
56:56subjects and our clinical in our
56:58clinical population. The rate of
57:00trauma is really high and so I just
57:03be curious what you would learn.
57:15Oh
57:18sorry, I turn my camera off 'cause
57:21my feed doesn't sound great.
57:23I think what I heard was asking about
57:27trauma information in our population and we.
57:31The Childhood Trauma questionnaire.
57:33As part of our pre screening and
57:35there's no exclusion for trauma,
57:37so we think that those are appropriate
57:40patients to come to this study.
57:42Barring any of the other exclusions.
57:44But we think this could be a good
57:47fit for some of those patients.
57:50I guess I was a little curious
57:53like what is the rate of your subjects
57:57reporting some significant trauma?
57:59I wasn't suggesting that they be excluded.
58:01I was just curious what
58:02you learned about them.
58:05Sure, I mean in our first study,
58:08the rate was relatively low and I think
58:11part of that was an outpatient study.
58:14Many of the people that found us
58:18found usthroughclinicaltrials.gov.
58:18It was a more affluent population,
58:21so those rates were relatively low.
58:27We're going to work harder to get the
58:29word out for these newer studies,
58:31and so I would expect that it would be
58:34a higher rate in the upcoming study,
58:37but that remains to be seen.
58:42I guess I I guess it's 2:00 o'clock,
58:44so I guess people who need to jump
58:46off should please jump off and
58:48not feel bad about jumping off.
58:50I'm wondering, can we stay on to answer
58:52a few more questions if people have them.
58:55Metal OK. We're not going to be too sure.
59:00OK, we're gonna I guess Larry
59:02Villanos I know still on 'cause I
59:04can see him on camera so I was hoping
59:06he could ask his question.
59:10Yeah, just first of all Jenny.
59:12That was an amazing talk really.
59:15You're so clear and concise and I
59:17just learned a lot and you know,
59:20so proud of you.
59:21So I was wondering about the
59:23recreation appeal of CADA mean.
59:25You know, Special K and and
59:27what it is an in the population.
59:30It just made me think are there individuals
59:33out there who are self medicating?
59:35You know, with the with the abuse
59:38of cada mean in your opinion.
59:40Never thought about this before your talk
59:42and I just I just wondered about that.
59:46Yeah, I think it's a great question.
59:48We I was recently doing a conference,
59:51a virtual conference at Oxford
59:52with Academy Group and there was
59:55a presenter there that was talking
59:57about Kennedy and use patterns in
59:59various places across the globe.
01:00:00And we talked about this idea of whether
01:00:03there's a component or a proportion
01:00:05of people that are self medicating.
01:00:07And I think you know that maybe that
01:00:10may be the case of particularly as
01:00:13the news has gone out that this is.
01:00:16Can be a helpful thing.
01:00:18I would imagine that that might
01:00:21you know increase further and
01:00:23there are certainly hypotheses.
01:00:25About you know folks that use
01:00:27psychostimulant recreationally that
01:00:29have undiagnosed or undertreated ADHD,
01:00:31so I think you know.
01:00:33Thinking about self medication is
01:00:35A is a good thing to keep in mind.
01:00:39And
01:00:39what was the original attraction
01:00:41as a regulation of drugs? I mean,
01:00:43what's the appeal of dissociating or?
01:00:47I don't know if I have
01:00:49a great answer to that.
01:00:51I mean, I think some people are
01:00:53just interested in altering
01:00:54their experience and maybe what
01:00:56one person would find pleasant.
01:00:59Another person would find very unpleasant,
01:01:01but I'm not sure. I'm not sure.
01:01:05OK. Thank you.
01:01:09I guess I'm gonna, I think also would be
01:01:12worth just mentioning what the stuff we
01:01:14do to prevent the abuse of the Academy
01:01:17were giving subjects in the study.
01:01:19Is that way there's no take home cada
01:01:21mean and fairly all the treatments or
01:01:23are given in a clinic based setting.
01:01:26And that's true of the provider.
01:01:28The FDA medication too.
01:01:29I guess I'm going to call and
01:01:31Emily Olson next.
01:01:32She had a question in the chat.
01:01:38Great talk Jenny.
01:01:39I was just thinking about I
01:01:42read a New York Times article
01:01:45yesterday that talked about a
01:01:47study done in adults in PTSD
01:01:49where they found that MDMA.
01:01:54Made it was effective when combined
01:01:56with therapy in helping PTSD and
01:01:58as I was listening to your talk
01:02:01and thinking about what you were
01:02:03saying about this after cada mean,
01:02:05like taking advantage of that
01:02:07period using in depression and kids.
01:02:09I was just thinking about whether
01:02:11Cada mean is going to be a part
01:02:14of kind of a group of medication,
01:02:16some kind of new medications
01:02:18and I was wondering,
01:02:20given your expertise and you
01:02:22know a lot about this weather.
01:02:24What your thoughts were on this?
01:02:28And kind of what you thought
01:02:30the future would be. And I mean,
01:02:33I think it's amazing how quickly you're
01:02:35you're now studying this in kids,
01:02:37which I think is wonderful,
01:02:39and whether these other treatments
01:02:40I know there's a lot of talk
01:02:43about psilocybin as well.
01:02:44What your thoughts are about
01:02:46kind of bringing these as these
01:02:48developments come in adults,
01:02:49seeing if they also help kids as well.
01:02:52Whether it's depression,
01:02:53anxiety, PTSD, etc.
01:02:56Yeah, I mean it's a great.
01:02:58Question, and I think I read the same
01:03:01article that you did and you know,
01:03:03I think the folks that are studying
01:03:05psilocybin and maybe MDA may as well have
01:03:08kind of a different attitude about it
01:03:10than a lot of the Academy researchers.
01:03:12And I don't quite know why that is.
01:03:15But you know, I think the.
01:03:18Experience is a key part of the
01:03:21therapeutic ingredients for the MD,
01:03:22MA and psilocybin studies,
01:03:24whereas I think a lot of the CADA
01:03:27mean studies folks kind of view
01:03:29the experience as like a nuisance.
01:03:31And like if we could build
01:03:33a better mousetrap,
01:03:34we would not have the experience.
01:03:36I think even the choice of Esketamine
01:03:39with Janssen they thought OK,
01:03:40this has less dissociated stuff.
01:03:42It binds tighter Dan and MDA.
01:03:44You know the best cada mean would have
01:03:47nothing and so it's really a difference.
01:03:50A different way of viewing
01:03:52things and there's, you know,
01:03:54some evidence for and some against on,
01:03:57the dissociative experience
01:03:58correlating with treatment efficacy.
01:03:59So there's some data sort of on both sides,
01:04:03so in a way I think they are sort of
01:04:07all in this bubble of, like you know,
01:04:10rediscovered or newly appreciated.
01:04:12Medications that had some kind of stigma
01:04:15attached to them before that are now
01:04:18being re explored in rigorous contexts.
01:04:20I think in terms of like
01:04:24translating things into Pediatrics.
01:04:26You know, I feel like.
01:04:28I mean has a history.
01:04:32Nervous, the other types of things
01:04:34that really don't have a pediatric
01:04:37safety history or use ever,
01:04:38so I don't think I would be at the front
01:04:42of the line to be doing those studies,
01:04:45but I think for all of these types of things
01:04:49it's like a risk benefit analysis, right?
01:04:52If someone has tried everything that we
01:04:54have and nothing has worked, including ECT.
01:04:57Think it's hard to make an
01:05:00argument that if they're really,
01:05:02you know, want to try something,
01:05:04especially in like a clinical trial context,
01:05:07you know.
01:05:07These are risk benefit discussions
01:05:09and reasonable people can disagree so,
01:05:11but it's a very interesting area.
01:05:13I think in terms of just ethics
01:05:15and trial design and access.
01:05:24It.
01:05:30Jenny, we lost you Jenny.
01:05:34The. But I will.
01:05:37I guess I'll step over the silence and
01:05:41then just say that I think we people.
01:05:45OK yeah, I think you're back.
01:05:48Let's see or I will.
01:05:50I think we're going to have
01:05:53to wrap up in a second,
01:05:55but by it's a big thing is that we've
01:05:57both been very hesitant to look at
01:06:00the other psychedelic medications.
01:06:01'cause I think there's already
01:06:03one of the issues with cada mean.
01:06:05And as Academy that seem like
01:06:07they're very promising treatments.
01:06:08Or the. The cavalier nature of it.
01:06:15I just think it mean is so much better
01:06:17if the data profile than the other
01:06:20medications at the moment or the
01:06:22drugs both in terms of efficacy and
01:06:24safety than it would really get it.
01:06:27It may. It may hurt the credibility
01:06:29of some of the research to to go
01:06:32after other stuff prematurely.
01:06:36And then also, there's just such a need
01:06:39to combine the treatments with the with
01:06:42the evidence based psychotherapies.
01:06:46Yeah, I don't know if folks in here,
01:06:48me or not. My Internet
01:06:50is going on strike today.
01:06:52Hear you with your pictures off. We
01:06:55can hear you. Yeah, OK good yeah.
01:06:57I mean I couldn't agree more with Michael
01:07:00and that you know a big part of our
01:07:02efforts I think should also be just
01:07:04getting the things that we already know.
01:07:07Work to the people that need them.
01:07:09You know, a good solid psychotherapy
01:07:11or reasonable SSRI trial.
01:07:12I think in some ways.
01:07:15I've taken for granted that that's you
01:07:17know that that's readily available.
01:07:19I think a lot of times it isn't,
01:07:22and so expanding acts.
01:07:24To our. The.
01:07:30They make. I think the Internet gods
01:07:33are telling us to wrap this up soon.
01:07:36But I just wanted to thank you for
01:07:39talking and thank the Internet gods for
01:07:41for it holding out on us the whole time.
01:07:44So until now and then we could.
01:07:47We got through the talk and you did an
01:07:50excellent job and Internet connection
01:07:51just went bad at the end, but.
01:07:55Excellent job and please feel free
01:07:58to email Jenny with any other OK.