Child Study Center Grand Rounds 09.21.2021

October 29, 2021

Prenatal Maternal Depression and Antidepressant Exposure - Neurodevelopmental Trajectories

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02:24Hey Jonathan, can you hear us? Let
02:28me introduce you to two
02:29people you've never seen.
02:30One is Doctor Jayme Mcpartland.
02:32Dr Taking what do you want to
02:33start talking with our speaker?
02:34We haven't let people into the room yet.
02:39Hey Jonathan, do you want to have a really
02:41publicly broadcast ketchup session?
02:45Sounds great. Good, you know.
02:50I had to admit I didn't notice
02:52telling your side just now.
02:53By the way, Jamie, Jamie eye contact.
02:57Yeah, that's correct.
02:58I didn't notice it.
02:59Said Duke University is that yeah.
03:02I mean he he doesn't know in autism.
03:04We don't make eye contact.
03:06Normally developing people would make typing.
03:08Yeah, I know,
03:09but as an autism eye contact specialist,
03:11we've ruled that eye contact being
03:13meaningful during zoom settings.
03:15So it's like saying I mean,
03:16in fact I can communicate
03:18effectively like this.
03:19And then when it's time,
03:20so when did you make the move?
03:23September 1st, so
03:24it's brand new. Congratulations
03:26very exciting. Are you physically there? Yeah
03:29yeah yeah I came down with my
03:31family over the summer so we could
03:33get our kids set up at school.
03:36Yeah yeah thanks yeah.
03:38And I'm I'm really excited about being here.
03:39It's been really great so far
03:41that is is really yeah I
03:43want to hear all about it.
03:44Yeah for sure not broadcasting
03:46to the entire Child Study Center,
03:49right? How are your kids doing?
03:52I'm good that great school is in person.
03:56They're happy, started high school in,
03:58started high school this year.
03:59So so far, so good. Now you did you.
04:02Are you still on CPD? Yes I am I
04:05I'm done. I
04:06know you graduated. You will be.
04:08You will be greatly missed.
04:12I will enjoy the break but
04:13I will miss it too, yeah.
04:16Oh, you're you finished up.
04:20You were you were on the Zoom study
04:22section for one or two sessions.
04:24Is that right? Yeah, yeah.
04:26For the time being, we're continuing on
04:28zoom, which is, I find, a bit painful.
04:31It is it makes for a very long day.
04:33Yeah, yeah, I thought you're gonna
04:36say my timing was good because they
04:37did away with continuous submission.
04:39So I actually meant to thread
04:40the needle in terms of period
04:42of time for continuous submission.
04:46I I didn't know that they got
04:47rid of continuous emission.
04:48If I if I'm not mistaken,
04:50I thought they changed the policy.
04:53OK, I didn't really thought. But
04:55now I'm going to inquire about some protocol.
04:58So what Andres, what's the what's
04:59the is when we want to start?
05:14Where's your schooling?
05:47Kids.
05:54The people.
05:57They can only hear it.
06:04Sure.
06:06Remember the test. Unless.
06:22OK, silly.
06:25Epic.
06:28And I can see your cat.
06:31Do you want me to start letting people in?
06:36While he's talking just because,
06:38well, who is wow? Yeah,
06:43just because critics are perfect
06:45is over there with translating,
06:47but right now we're going
06:48to start with it. Yes, OK?
06:54Yeah, it's.
07:05Very sophisticated plan for managing
07:07your question and answer session.
07:09I promised that I will screw it
07:11up and so I apologize in advance.
07:15Make room for Kyle.
07:19Sharp
07:22so did people type their questions
07:24into the chat function today?
07:26They will get to ask and they will
07:29be able to ask in person. Yeah.
07:40That's.
07:44Rights. Oh, because I asked.
08:02Introduction.
08:22Yes.
08:35I think we're good. Well,
08:37everyone. Welcome to today's grand rounds.
08:41My name is Mike Crowley.
08:42I'm a member of our Grand rounds committee.
08:44Last week we heard from Carol,
08:46I just want to remind everyone
08:48before I introduce Dr.
08:50Mcpartland that I that we have
08:52compassionate care grand rounds next
08:53week and the title of that grand
08:55rounds is refractory providers and
08:57systems come together to care for a
08:59severely depressed and suicidal youth.
09:01So out further ado.
09:02Doctor mcpartlin.
09:08Hey welcome everyone.
09:09Today it's my pleasure to introduce Doctor.
09:13Jonathan Posner is a child and
09:16adolescent psychiatrist and
09:17vice chair for research in the
09:19Department of Psychiatry at Duke,
09:20which is news hot off the
09:23presses as of September 1st.
09:25He directs pediatric brain imaging
09:28laboratory that has maintained
09:29consistent NIH funding since
09:31founding over ten years ago.
09:32His research focuses on neuro
09:34development with an emphasis on
09:35imaging approaches to studying
09:37neurobiological correlates of mental.
09:39Illness and cognitive development
09:42is Pi on 312 N family based
09:45studies aimed at understanding
09:46the influence of family history.
09:48Psychosocial adversity in prenatal
09:49exposures on the development of neural
09:51circuits involved in executive functions.
09:53In emotion regulation.
09:55You know, having reviewed the CD,
09:56he's a piece of many,
09:58many more grants than that he's an
10:00extremely productive researcher.
10:01His work has been published in leading
10:03journals including JAMA Psychiatry,
10:05John Pediatrics, Pediatrics,
10:06Lance Psychiatry in The Lancet.
10:08He's a.
10:09A very engaged mentor and educator and has
10:12served mentor to many new junior faculty,
10:14postdocs,
10:15and psychic residents who've done well.
10:19Came to know,
10:19gentlemen,
10:20through our mutual serving on
10:22a study section,
10:23childhood safe theology and
10:25developmental disorders,
10:26and one of the things that I
10:28recognized by Jonathan isn't in
10:30addition to having deep technical
10:32knowledge of his methods.
10:33He also has very strong clinical
10:36sense and is extremely thoughtful.
10:38And so I'm really looking forward to
10:39hearing what he has to say because
10:41I I think it's gonna actually
10:42even be more rewarding with his
10:45comments during study section.
10:46If you can believe it or not,
10:47and he's going to be talking about.
10:49Kind of depression and
10:50antidepressant exposure,
10:51and how that influences
10:53neurodevelopmental trajectories.
10:54Thank you so much,
10:55Jonathan.
10:57Thank you so much Jamie. UM,
10:59really appreciate that introduction.
11:02And I just wanted to mention that it's a.
11:04It's such an honor to be
11:06presenting to you all as a child,
11:08not a lesson psychiatrist I I never did any
11:11of my own training at at Yale Child study,
11:15but so many of the the mentors
11:17who taught me so much about child
11:19psychiatry all grew up at Yale,
11:21so the Child Study Center is
11:23always loom very large in my mind,
11:25so the real treat to be
11:27presenting to you all today.
11:29Uhm, so I'm going to be talking
11:32today about the safety of
11:36antidepressant use during pregnancy.
11:39And specifically the use
11:41of SSRI antidepressants.
11:43Uhm, and this is a topic that I
11:45I really find quite interesting
11:48because on the one hand it's it's
11:51a question that we want very,
11:52very badly to know the answer to.
11:54We want to know whether we can
11:57safely prescribe these medications.
11:58And yet we are somewhat hamstrung in
12:00how we how we approach this question,
12:03because the most rigorous methodology
12:05that we would have to answer this would
12:09be a randomized clinical trial and for both.
12:13Uh,
12:13and pragmatic regions.
12:15It would be very,
12:16very difficult to to use that methodology,
12:19so we're left in this situation
12:21where we want a definitive answer.
12:23And yet our our approach is somewhat limited.
12:26I'm going to be talking to you today
12:28about how we're trying to tackle this
12:30problem in lieu of those limitations.
12:36Uh, so some some disclosures to mention.
12:39So I have received research support
12:42from Shire which is now part of the
12:45Cada Avino mix and Innovation sciences.
12:48But none of that research support
12:51was related to the data that I'm
12:53gonna be presenting to you all today.
12:56Uhm, so uh before getting started,
12:59uhm, I first wanted to discuss two
13:04foundational concepts that really guide my.
13:08And the first is the
13:11centrality of development,
13:13and I was essentially axiomatic that most,
13:17if not all mental illness.
13:21Has it had development to origins
13:23or or to put that another way
13:27that I think if we really want to
13:29understand the etiology of psych.
13:32We have to understand development,
13:34but development is of course difficult.
13:38Not only now are we are we trying
13:41to understand this incredibly
13:43complex organ in the human brain,
13:46but when we take a developmental perspective,
13:49we're now chasing after a moving target.
13:52As the brand grows and matures.
13:57The second principle that guides
13:59my work is the importance of.
14:01It's all of our approaches to
14:03understanding the brain and
14:05mental illness have limitations.
14:08Whether it be preclinical models for example.
14:17Relation based research
14:18epidemiology that have.
14:23Clinical samples may have
14:26limited generalizability.
14:27But when translational science
14:28is really working at its best,
14:31we're able to triangulate across
14:34these domains, and that's when I
14:36think we can really make progress,
14:38and my hope is that.
14:40By the end of this talk,
14:42I've convinced you.
14:45That the story of prenatal SSRI
14:47exposure is 1 where this trend?
14:55By giving you some background on depression
14:58during pregnancy to provide some context
15:01for why antidepressant use during
15:03pregnancy is such an important topic.
15:06So to begin, UM, depression
15:09during pregnancy common,
15:10it's estimated that anywhere from
15:1310 to 20% of women will experience
15:16depression during pregnancy,
15:18and then there are a host of associated
15:21risks that go along with that.
15:23So, first and foremost is the
15:25depressed and anxious mood.
15:27But the suffering of the depression
15:29experience by the by the individual.
15:32But then there are a host of
15:35other potential complications.
15:36So one is that, UM,
15:38prenatal depression is associated
15:40with worse prenatal care,
15:42poor nutrition.
15:44An increased risk for substance
15:46abuse and suicide.
15:48There's also concerns about premature
15:50delivery and low birth weight.
15:53A another growing concern is that
15:56prenatal depression may increase
15:58stress hormones and have trickle down
16:01effects on the fetus by altering
16:05the intrauterine environment.
16:07And then last but certainly not least,
16:09is that prenatal depression is really
16:11a set up for postpartum depression,
16:13which can have negative effects on
16:16the parent infant interaction with
16:19downstream effects on neural development.
16:24So if a pregnant woman develops
16:27depression and discuss his
16:28treatment with her doctor,
16:30it's really important to keep
16:32in mind that this decision,
16:34the treatment decision,
16:35is really a balancing act.
16:37The the physician and the pregnant
16:39woman are trying on the one hand
16:42to weigh the negative effects of
16:44the depression while at the same
16:47time considering potential risks of
16:49prenatal antidepressant exposure.
16:50And when I say enter the present.
16:52Oh sure, I'm referring primarily
16:54to SSRI exposure,
16:55and I'll show you later that's the
16:59primary medication class that's used.
17:01Uhm, and the SSRI.
17:03Exposure to the fetus really is not trivial.
17:06These medications readily
17:08pass through the placenta,
17:10and it's estimated that their levels in
17:13fetal circulation are anywhere from 70
17:15to 80% of that of the maternal levels.
17:20Safety concerns have come up over the
17:24years with a variety of FDA warnings.
17:28But most of these concerns
17:30have been put to rest,
17:32or at least these concerns have
17:34seemed far less significant than
17:36the risk of untreated depression.
17:40And as these safety concerns have subsided,
17:43prenatal SSRI use in EU.
17:45S has steadily increased.
17:47So what I'm showing here is the
17:50percentage of pregnant women taking
17:52an antidepressant in EU. S. Overtime.
17:55Then you can see this steady increase.
17:57The top line here.
17:59Is any antidepressant and the
18:01next line down is of those.
18:03The percentage of SSR eyes and
18:05so you can see that the Lions
18:07sharing enter depressant prescribed
18:09during pregnancy are indeed.
18:11SSRI, enter the presence.
18:14And so we're now at a point where
18:17SSR eyes are used by anywhere from 4
18:21to 8% of pregnant women in the US,
18:24and that translates to anywhere from
18:26160 to 320,000 babies born each year.
18:31In EU.
18:32S who have been prenatally exposed to SSRI's.
18:39So now that I've I've given you
18:41some of the clinical context
18:43regarding SSRI use during pregnancy,
18:46I want to shift to the second part
18:48of my talk where we move from the
18:51clinical setting to the bench or
18:53do basic neuroscience research and
18:56starting in the early 2000s Neuro
18:59Neuro scientists started trying to
19:02use preclinical models to understand
19:05how SSR eyes are effective.
19:08And at the most proxamol level,
19:11we have a pretty good sense of how they work,
19:14so you have your presynaptic and
19:17postsynaptic neurons and SSRI's
19:19block the transporter that reabsorb
19:21serotonin from the synaptic cleft
19:23from the synaptic cleft.
19:27So one approach that was used
19:30early on to try to understand how
19:33SSRI's work was the transporter,
19:36knockout mouse and the idea here.
19:39And this was work done in
19:41large part by J Gingrich.
19:43The idea here was that it's
19:46SSRI lock the transporter,
19:48then simply removing the transporter
19:51should mimic those SSRI effects and
19:54essentially creating a highly resilient
19:56mouse or or a type of mighty mouse.
20:01And what's quite interesting is that
20:03that's not at all what was found.
20:06Uhm, instead of a less anxious mouse,
20:09the knockout mouse actually displays more
20:13anxious like behavior and an example of
20:16that is using the latency to feed paradigm.
20:20So what you see here is a mouse in
20:23a cage with a tasty food pellet
20:25in the middle of the cage,
20:27and the investigators measure
20:28how long it takes for the mouse.
20:31To get up the courage to go into the
20:33middle of the cage and and eat the
20:35treat and so first you see the latency
20:38to feed in the the wild type mouse.
20:41Uhm and then come with a mouse have been
20:44pretreated with the necessary you see,
20:46a decrease in the latency to feed.
20:48So in other words the mouse gets up the
20:51courage sooner and it goes into the
20:53middle of the cage and eats the pellet.
20:55Uhm, but with the knockout mouse you
20:58actually see this increased latency.
21:00So surprisingly,
21:01it actually takes that in-house,
21:03longer to get up the courage to go and
21:07explore the middle of the of the cage.
21:13Uhm? And I realized that I'm being
21:16a bit loose in my my language here.
21:19When I when I say I'm out
21:20getting up the courage.
21:21Obviously I'm not meeting that literally.
21:23What I mean really is anxious like behaviors.
21:27Uhm? And so this finding has
21:29actually been replicated.
21:30Now many, many times what I'm showing
21:33the slides here on the left these are.
21:37Brain slices that are staying for
21:39this for the serotonin transporter
21:41and the wild type you see that the
21:44transporter is relatively ubiquitous
21:45across the the mouse brain,
21:47and then on the slide on the right
21:49it's entirely absent, so the the
21:51knockout process does indeed do it.
21:53It's supposed to do.
21:54And then, in terms of behavioral phenotypes.
21:59What I described previously was
22:01to increase latency to feed,
22:02but there's also increased anxiety
22:04like behaviors on an open field test,
22:07there's increased stress responsivity,
22:09increased social avoidance,
22:11and increased sensitivity
22:12to alcohol and to cocaine.
22:19Now, this finding of increased
22:21anxiety and depressive like behaviors
22:24is somewhat paradoxical because if
22:27SSRI's or disabling the transporter,
22:29then why should it be that
22:31removing the transporter should
22:33actually have the opposite effect?
22:36And to answer this is where having a
22:40developmental perspective is so so critical.
22:43So if we think of the,
22:44the knockout mouse is having the
22:47transporter removed from the gecko,
22:49so there's increased serotonin
22:51signaling from conception all
22:53the way through development.
22:55And what the FINA?
22:56The behavioral phenotype that
22:57we see is increased, anxious,
22:59and depressive like behaviors.
23:01The story is quite different
23:03with an SSRI treated.
23:07A mouse where you expose the mouse
23:09to an SSRI later in development
23:12and therefore only have increased
23:14serotonin signaling on a much
23:16more mature brain and see a
23:18different behavioral phenotype.
23:23So this, UM, this sort of developmental
23:26insight LED Mark answer Key and
23:29others to conduct a really elegant
23:32series of experiments where they
23:34asked what would happen if you
23:37block the serotonin transporter over
23:39distinct periods during development.
23:41And so using an SSRI in this case Prozac,
23:45they blocked the transporter in mice
23:47at different developmental stages,
23:49and then probed the anxious and
23:51depressive like behaviors in
23:53these mice during adulthood.
23:57And what they found was that
23:59if they blocked the transporter
24:01during the adult period during post
24:04day to post Natal Day 90 to 190,
24:06they did not see this increased in
24:09anxious or depressed like behaviors.
24:11Similarly, post data 21 to 41.
24:15And it was only in this relatively
24:18narrow window window that they saw that
24:21adult phenotypes increased anxiety from
24:24post Natal Day two to post Natal Day 11.
24:31So. Uhm? If we now translate that
24:38period into the human analogue.
24:40That period of post Natal Day
24:43two through post Natal Day 11,
24:45translates into the third
24:47trimester gestation in humans.
24:50So the prenatal period.
24:54Mark and others then went on to show
24:57that this early increase in serotonin
24:59signaling caused abnormalities in
25:01morphology and electrophysiology,
25:04and the informit cortex as well as.
25:08Alterations in theater learning.
25:15So now, uhm. The question that we
25:17need to ask is why should serotonin
25:21signaling have such different effects
25:23depending on the stage and development?
25:29It occurs the answer to this
25:32question is still somewhat unknown,
25:34but it likely relates to the
25:36functional role of serotonin changing
25:38over the course of development.
25:40So in adulthood, serotonin acts
25:42like a canonical neurotransmitter,
25:44but during the fetal period serotonin
25:46seems to act more like growth factor
25:50influencing neuronal proliferation,
25:51migration as well as the
25:54organization of early neurons and.
26:00My favorite example of this
26:02comes from Pat Leavitt's lab,
26:04where they found that the actual
26:07direction of axonal growth and can
26:11actually be reversed depending
26:13on serotonin concentrations.
26:16The mechanisms underlying how serotonin
26:18function changes over development
26:19are still being worked out and
26:21not within the scope of this talk,
26:23but there is a lot of really interesting
26:26work being done in this area,
26:28and I provide a reference here
26:29for those who are interested.
26:34So I now want to take you to
26:37the next part of the talk,
26:39so we've gone from the clinic where we
26:42talked about the increase in the use of
26:45SSR eyes during pregnancy to the bench,
26:48where we learned that at
26:51least in a preclinical model.
26:54Prenatal exposure to accessorize seemed to
26:57have long lasting our development effects,
27:00but the question now is,
27:02does this have any relevance to humans?
27:05And to answer this question,
27:07we're going to move from the bench to
27:10population studies or epidemiology.
27:14So I'm going to take you on a trip
27:18across the Atlantic to Finland.
27:21And Finland is really an extraordinary
27:23place to do epidemiologic work,
27:26because their health system
27:28tracks their health system,
27:30has a national registry where they can
27:33track all citizens from from birth forward,
27:37allowing investigators such like Andre
27:40surrender to look at the effects
27:43of exposures at a population level.
27:47So using this finish register registry,
27:50Andre and his colleagues were able
27:52to identify 60,000 infants who
27:54were born between 1996 to 2010.
27:57And then they stratified that sample
28:00into 33,000 who were born to healthy,
28:03nondepressed mothers.
28:0410,000 born to mothers with
28:07a diagnosis of depression.
28:09And then another 17,000 born to
28:13mothers who had a psychiatric illness
28:15and used an SSRI during pregnancy.
28:20And here's what they what
28:22they found and this slide.
28:24I realize it's a. It's a bit busy,
28:25so let me walk you through it.
28:28So what we're looking at here
28:30are four different outcomes in
28:32the children and the top left.
28:34The outcome is depression,
28:35and these are the percentage of
28:37children who develop depression,
28:39and these are the ages of the children.
28:41So as you move from from birth
28:43all the way up to 14 and you
28:45see there's this increase in
28:46the prevalence of depression.
28:48The top line has the infants
28:51who were exposed prenatally to
28:53SSRI's and you can see that that
28:56group is significantly higher
28:58than all the other groups.
29:01The other groups that they looked at were
29:04infants who were exposed to a maternal
29:08psychiatric illness during pregnancy,
29:10but with no medication.
29:12You see that in blue and yellow
29:15you have mothers who discontinued.
29:19SSRI before becoming pregnant.
29:23Uhm and and and then the black.
29:26You have a healthy control group.
29:30So there's a few things to note about this,
29:33so one is that the effects surprisingly
29:36seems to be somewhat specific,
29:38and that we see the effects of.
29:40On depression outcome but we don't see
29:42those effects for anxiety disorders,
29:45autism or ADHD.
29:46We don't see separation across the groups.
29:49And also the stratification that they use.
29:54Controls for the the presence of
29:57psychiatric illness in the mother.
30:00So it's unlikely to be attributable to.
30:04Prenatal psychiatric illness alone.
30:09Uhm? So this finish epidemiologic
30:11study is consistent with the
30:14preclinical findings that I showed you.
30:17But there really are some critical
30:20limitations that are that are
30:22important to be mindful of.
30:24First and foremost,
30:25there's a problem of what's called
30:28surveillance bias and what that refers to is.
30:31The idea that if they if a pregnant
30:34woman developed depression goes
30:35to her doctor and decides to
30:38take an anti depressant.
30:40That woman,
30:40when she becomes a mother may be
30:43more likely to notice depression
30:44and her offspring and bring her
30:47offspring to see a a physician
30:51rather than relative to a woman
30:53who who's depressed but does
30:55not seek SSRI treatment.
30:59The second issue is post Natal factors.
31:03So the finish study really did
31:05not address post Natal issues,
31:07so it's possible, for example,
31:09that the SSRI exposed group also
31:12experienced more negative post
31:13data exposures and these post Natal
31:16exposures were really driving the
31:18outcomes rather than the SSRI per say.
31:24And then the third limitation,
31:26and this is really a critical
31:27one in a really difficult.
31:30It's called one to address.
31:31This is called confounding by indication,
31:33and this is an issue that I'm going to
31:36continue to refer to later in the talk.
31:38This compound refers to the idea
31:39that there could be something
31:41systematically different about the
31:43mothers who took SSRI during pregnancy.
31:46So, for example,
31:47there might be some reason why
31:49those mothers were prescribed
31:51SSRI's versus the mothers who had
31:53depression and were not prescribed.
31:56Perhaps, for example,
31:57they had a more severe depression,
31:58and that's really what was
32:00driving the finding.
32:04So to try to address these
32:07limitations, I'm going to.
32:08I'm going to take you back to the
32:11clinic to a clinic based study
32:13that that we recently completed
32:15where we tried to address at least
32:18these first two limitations.
32:23So this is a an infant MRI study
32:26that we completed at New York
32:29Presbyterian Hospital where we
32:31recruited pregnant women from the OBGY
32:34and clinics at New York Presbyterian.
32:38We then conducted prenatal diagnostic
32:41and medication assessments and anywhere
32:45from 19 weeks to 39 weeks gestation.
32:48And then we stratified the
32:50women into three groups.
32:51So we had our healthy control
32:53group with no psychiatric illness.
32:55Are group of women who developed
32:58who are experienced depression
33:00during pregnancy but did not take
33:02medication and and then our SSRI group?
33:08We then obtained MRI scans on their
33:12babies at about 3 1/2 weeks of age.
33:15These were non sedated infants
33:18naturally put to sleep.
33:20And we covariate for intersex
33:23agents can birth weight and any
33:27post Natal depressive symptoms.
33:30So the strength of doing MRI scanning
33:33so early in life is that it limits the
33:37possibility of post Natal exposures.
33:40So we're essentially phenotyping
33:42the brain prior to the infant
33:44having many post Natal exposures
33:46by virtue of the young age.
33:51And this is work that was
33:53spearheaded by Claudia Lugo.
33:54Condo lesson juchau that they
33:57published in JAMA Pediatrics in 2018.
34:00So what do we find?
34:03So there's a couple findings that I
34:05I want to draw your attention to.
34:08Using structural MRI and
34:10looking across the whole brain,
34:13we found that the prenatally
34:16exposed babies had.
34:21Really two important findings.
34:23One was an increase in the
34:25volume of the right amygdala,
34:27and that was above and beyond what
34:28we saw in the depressed only group,
34:31and the healthy controls.
34:33And then similarly we saw a volume
34:35increase in the right amygdala,
34:37again in the SSRI group above,
34:39and beyond what we saw in
34:41our two comparison groups.
34:45We then looked at a diffusion tractography
34:49to look at white matter connectivity
34:52and again here we looked across the
34:55whole brain and unbiased approach.
34:57And and we found that there were four
35:01white matter connections that were
35:04increased differentially in the SSRI group.
35:07And what was most striking and that is that.
35:12The similar to the structural MRI findings
35:15we found increased connectivity between
35:18the right amygdala and the right insula,
35:21and that's displayed here in the
35:23violin plot again in the SSRI group,
35:25but not in our two comparison groups.
35:30So while these findings are consistent
35:33with what we would expect from the
35:35preclinical data that I showed you,
35:37as well as the population
35:39based study in Finland,
35:40they're not without important limitations.
35:44So first and foremost,
35:45our sample size was quite small.
35:47We only had 16 babies who were
35:49prenatally exposed tests, or I.
35:51Second, we still haven't addressed this
35:53issue of confounding by indication,
35:55which again I'm going to.
35:56I'm going to come back to 3rd.
35:59We had no in this study.
36:00We had no behavioral follow-ups,
36:02and we really don't know the behavioral
36:05significance of our MRI findings.
36:07And then, third importantly,
36:09there were really striking demographic
36:12differences across our samples.
36:14So if we looked at the SSRI group
36:17versus the depressed but no SSRI group,
36:20the SSRI group was significantly wealthier.
36:24We can't know for sure why that happened,
36:26but we assume it relates to access to care,
36:29and we of course tried to control
36:31for this and our analysis.
36:33But when the when the difference
36:34is that stark,
36:35there's a limit to what you can control.
36:37Or just statistically?
36:42OK. So this brings me to our
36:46our current ongoing study which
36:48were conducting in Sherbrooke,
36:51QC and this is a collaborative project
36:54that we're doing with Larissa Taxor,
36:57who's a professor at the University
36:59of Sherbrooke and Adi Talati,
37:01who is an associate professor
37:03at Columbia University.
37:04And the first question that I
37:06always get when presenting this
37:08work is why are we doing this
37:10study in Sherbrooke and in Quebec?
37:13And there's a few reasons for that.
37:16One is that as many of you know,
37:19Canada has universal health care,
37:22so that issue that I described before
37:24having the demographic differences that
37:26we think we're related to access to care.
37:29We're hoping that by doing this study
37:30in an area with universal healthcare,
37:32that should no longer be an
37:35issue in our follow-up study.
37:37The second Sherbrooke,
37:39being in Quebec,
37:41is Quebec is the only French speaking
37:43province in Canada and as a result
37:46people who are born in Quebec tend to
37:48stay in Quebec and for anyone who's
37:51ever done birth cohort brief research,
37:54you really don't want people
37:55moving out of area and makes it
37:57much much harder to do followups,
37:58so doing this type of study
38:00in in Quebec is advantageous,
38:02and our collaborator lyrics attacks
38:04are Rana prior birth cohort study and.
38:07At 90% retention up into adolescence,
38:10which is really remarkable for
38:12that type of study.
38:14And then third,
38:15although Sherbrooke is a
38:17relatively small city,
38:18it has about 200,000 people.
38:20It's the tertiary Center for
38:22all of eastern Quebec,
38:24so their volume of deliveries
38:25is actually quite high.
38:27They get about 2000 deliveries per year.
38:32So in this new study we are going
38:35to be recruiting women during
38:37the first trimester of pregnancy,
38:40following them over the course of
38:42gestation while tracking their depressive
38:44symptoms and their medication use.
38:47Will then be scanning their babies
38:49with MRI at about one month of age
38:51and then continuing to follow the
38:53babies for the 1st 24 months of life.
38:57And there's really three aims
38:59that we're trying to tackle.
39:02The first is can we replicate
39:04our prior infant MRI studies
39:06regarding the amygdala and insula?
39:09Uhm, the second ummites determine whether
39:12there are any behavioral effects.
39:14So we'll be doing will be looking
39:17at behavioral effects related to
39:19emotion regulation in the babies
39:20at 12 months and 24 months,
39:22testing whether there's any effect
39:24of SSRI on those behaviors,
39:26and whether that relates to the
39:29MRI findings and then third,
39:32will be testing for post Natal modifyers.
39:36So, for example, does the parent.
39:40Infant interaction during the foot needle
39:42period does that alter our outcomes?
39:48So I want to return again to this
39:51issue of confounding by indication,
39:54because this is an issue that
39:56we really struggled with in
39:58trying to design this study.
40:00Uhm, and the you know,
40:02the only way to fully address this confound.
40:05If through randomization
40:07randomizing or a group of depressed
40:10women to either SSRI or SIBO.
40:12But we we felt that that
40:15would not be feasible,
40:16and the ethics of that would be
40:19would be somewhat questionable.
40:21So in lieu of randomization, uh,
40:23we're trying to carefully phenotype
40:26the the nature of the depression and
40:29the SSRI use throughout gestation,
40:32so we will be through remote tracking,
40:35will be tracking the pregnant
40:37woman's mood symptoms every
40:38two weeks throughout gestation.
40:41Beginning in the first trimester,
40:43and will also be quantifying SSRI
40:46exposure through pharmacy records.
40:48So I want to give you an example
40:50of how we're thinking about.
40:51That's so if you take this
40:54case as one example,
40:55if you have a a pregnant woman
40:57during the first trimester,
40:59her level of depressive symptoms are
41:01low and she's not taking an SSRI.
41:04Then during the second trimester
41:06her depressive symptoms increase.
41:07Still,
41:07no SSRI.
41:08And then during the surgery master she
41:11has high depressive symptoms and no
41:13SSRI that will be one case example.
41:16And then you might have another pregnant
41:18woman woman wear during the first trimester.
41:21She has both high levels of depressive
41:23symptoms and is taking a high dose of
41:25an SSRI during the second trimester.
41:27The depressive symptoms remain high.
41:29SSR eyes drop a bit third trimester.
41:32Her depressive symptoms drop
41:33and her SSRI use goes up.
41:38What we can do with with that level
41:41of granularity then is essentially
41:43create individualized areas under
41:44the curve to quantify the degree
41:47of exposure to depressive symptoms
41:49that that the fetus has as well
41:52as the degree of SSRI exposure.
41:55Uhm, and what we're hoping is that
41:58this approach should minimize the
42:00likelihood that there are systematic
42:03differences in the maternal depression
42:05across our different groups,
42:07or to the extent that there
42:09are systematic differences,
42:09will be able to quantify those
42:11differences and account for them.
42:18So this is a an R1 funded study
42:21that we launched in 2019.
42:24In our original plan was to have
42:28recruitment of about 350 women
42:30for the first 2.5 years of the
42:33study and then have our final
42:35assessments four to five years later.
42:38That timeline has unfortunately
42:39been significantly altered
42:40due to COVID where we were.
42:43We were shut down for a
42:44significant period of time,
42:46but our overall strategy.
42:49Remains the same.
42:51And another point that I want to
42:53make is that our our hope and our
42:56expectation from this study is not
42:59that will find that prenatal SSRI
43:01use is harmful or on the other
43:04hand that it's entirely benign,
43:07but rather that our study can aid
43:10women and clinicians when they're
43:12making decisions about whether to
43:14use antidepressants during pregnancy.
43:16So currently that decision
43:18as I mentioned before,
43:19really is a balancing act
43:22between various risk factors,
43:24but we really aren't clear
43:25about what those risks are and
43:28what those ramifications are.
43:29The decisions being made simply
43:32with far too many unknowns.
43:35And we think that whether or
43:38not we find neurodevelopmental
43:39effects of prenatal SSRI use these
43:42results will be helpful either way.
43:45So, for example,
43:46if we have find that the effects of
43:48the SSRI really are minimal on the offspring,
43:51this will allow clinicians to
43:53more confidently prescribe SSR
43:54eyes and will allow pregnant women
43:56to use them with with much less
43:59anxiety about their effects.
44:00Alternatively,
44:00if we find that there are significant
44:03effects or significant concerns that.
44:06This will steer the field towards
44:08towards other treatments for depression
44:11treatments such as psychotherapy
44:13or non serotonin antidepressants.
44:18Before concluding, I also I wanted to
44:21briefly mention some of the methodological
44:25challenges of doing infant MRI work as
44:28this was quite relevant to our study.
44:32So up here on the left hand corner
44:35I'm showing you infant MRI scans,
44:37T2 weighted MRI scans from the same child
44:40when the child was three weeks old,
44:42and then again when the child was 16
44:45months old and what I want to point
44:47out is that this was the same MRI
44:49pulse sequence and yet you can see
44:51the contrast in the brain differs
44:54quite dramatically and the reason
44:55for that is that the water content
44:58of the brain changes substantially
45:00over the course of development.
45:02And that causes major challenges when
45:06doing infant MRI research because
45:09most of our existing pipeline and
45:12approaches for doing MRI analysis
45:14are based on a mature brain.
45:16And so if you change the
45:18contrast dramatically,
45:19those approaches are going
45:20to become much less accurate.
45:24So this is one UM example,
45:27where an existing pipeline in MRI
45:31pipeline and automated software is used
45:34to segment the amygdala and infant brand.
45:37So each one of these pictures is
45:39a different amygdala that's been
45:41segmented from an infant MRI scan and
45:43what I want to draw your attention
45:45to is that there's the overall
45:47curvature does look like the amygdala,
45:49but there's bumps and ridges in this
45:51that are clearly not representing.
45:53Anatomy and are just in accuracies
45:56and in the processing.
45:58So we are trying to leverage
46:02artificial intelligence to improve
46:05upon these techniques,
46:07and so these are the results
46:10from our AI approach.
46:11Segmenting the amygdala
46:13in from infant MRI scans,
46:16and you can see it's it's
46:18certainly not perfect,
46:19but these types of bumps are are much,
46:21much less common in in our segmentation
46:24relative to the standard case.
46:27Another huge.
46:28Advantage of UM,
46:31that this artificial intelligence
46:33approaches the the computational time.
46:35So segmenting a infant brand
46:38using standard software,
46:39it takes up to 8 hours per MRI scan,
46:43and if you're working with,
46:44you know large datasets that can
46:46be incredibly cumbersome for
46:48artificial intelligence which
46:50can do the same operation about
46:52literally about 10 seconds.
46:54We've also measured the accuracy of
46:56our AI AI approach against a gold
46:59standard human tracing of the amygdala,
47:02and ours outperforms the standard techniques,
47:06and this is work that's being
47:08spearheaded by Yun Wang and Claudia Lugo.
47:10Can Dallas.
47:13Uhm? So in summary, UM,
47:17some of the lessons that we've
47:20learned in doing this work.
47:23I realize this is probably preaching,
47:25preaching to the choir,
47:27but first is the the the importance
47:29of development and not forgetting
47:32that the infant brain is is not only
47:35is not an adult brain, only small,
47:37or that the Physiology of the
47:39infant brain of the developing
47:41brain really can differ quite
47:43substantially from the adult brain.
47:47The second is the importance of
47:50translational research that all of
47:53our approaches have limitations,
47:55and what we really should be shooting for
47:58is triangulation across those modalities.
48:01Uhm, and speaking to that point,
48:03I I want to conclude with a quote from
48:06Michael Rutter who said it would be a
48:08great mistake to see translation simply
48:10in terms of applying at the bedside.
48:13The findings of basic science.
48:15Many of the pathways start with clinical
48:17studies and not with basic science and
48:20an even greater proportion involve a
48:22complex iterative interplay between the two.
48:24And it's that iterative interplay
48:26that I think we're we're really after
48:28in in many questions of psychiatry,
48:30but certainly.
48:31The safety of SS variety during pregnancy.
48:37So I want to acknowledge that the
48:39people that have supported this work,
48:41UM, NIH, UM, the Webster Foundation,
48:46several others, and really wanted to
48:48thank you for your time and attention
48:50and happy to take any questions.
49:05Thank you Jonathan. I don't
49:07know how it worked on zoom,
49:08but if you were here in real
49:09life people just clap for you.
49:10I want you to know that.
49:12No, thank you.
49:14But really excellent and elegant
49:16program of research you described for me.
49:19Really cool to see the kind
49:21of bringing together at the.
49:23From everything from very basic kind
49:24of animal work to stuff that's very
49:26very relevant and applied one second
49:29while we changed the view here.
49:34Jonathan, could you stop sharing? Sure yes.
49:43He sent over a share. OK,
49:44here you go,
49:45Jonathan. There we go.
49:49OK, so now my understanding is
49:52that people in the audience
49:54can actually ask a question with
49:56their own mouths if they would like.
49:58If they unmute, I don't.
50:00I don't know that anyone's unmuted yet,
50:02but I can go ahead and
50:04start with a question
50:06so. I thought it was really cool to see
50:09to get an understanding of the mechanism
50:11of how SSR eyes could be affecting
50:14prenatal brain growth from the mice,
50:16and it's really cool to see the differences
50:20that you saw in the the neonates.
50:23And I guess my questions are,
50:25I mean, another thing interesting
50:26is if I understood correctly,
50:28like the the mechanisms of what
50:30the authorized we're doing.
50:31It's not simply like there's just and
50:34there's too little, too little serotonin.
50:36It's a different structure,
50:37it's affecting around migration.
50:39So I guess my question is,
50:40is do the mice,
50:42the differences you see in the mice brains.
50:46I know that the structure is
50:47going to be different,
50:48but are they at least consistent
50:50with the differences that you see in
50:52infant brains and an infant brains?
50:53Is the pattern of kind of insula,
50:55amygdala enlargement and
50:57connectivity differences?
50:59Is that an established kind of neural
51:01phenotype for people with major
51:03depressive disorder in adulthood?
51:06Those are great great questions.
51:08Jamie. Thanks so much for that.
51:10Yeah, you know I. I think it's
51:13really fascinating to think that.
51:15The, UM, the Physiology of serotonin
51:17or or it's a it's a fax on the brain
51:21can differ so substantially depending
51:23on the developmental period that you're
51:26you're looking at and you know one of
51:28the things that I I didn't mention.
51:30Also is that expression of the
51:34serotonin transporter also changes
51:36substantially across development.
51:38So in the adult or mature brain the
51:40expression is somewhat circumscribed,
51:43whereas in the fetal and infant brain.
51:46It's it's rather ubiquitous,
51:47so it's it's expressed,
51:48although for the brain, and interestingly,
51:51it's also it's not in the adult brain,
51:54its expression is limited to
51:56serotine ergic neurons,
51:58which would,
51:58which would make sense given its role.
52:00But in the fetal brain it's
52:02expressed in neurons that that
52:04don't actually release serotonin.
52:06Again, speaking to the more plausible
52:09role of serotonin as a neurotrophic
52:12factor rather than a neurotransmitter.
52:15Uhm, but to answer the other
52:18part of your question.
52:20So I I guess I would say yes and no,
52:23UM, so certainly,
52:25UM,
52:25the the behavioral phenotype that
52:28they're seeing in the rodent models
52:32relate to emotion regulation and
52:35what we saw in our Internet MRI
52:37scans the effects and the amygdala.
52:39The campus,
52:40certainly those are heavily
52:42implicated in emotional responses
52:44or emotional responses in how we
52:47respond to various emotional stimuli.
52:49So there's there's consistency.
52:51There.
52:52Uhm,
52:52where there's less,
52:53consistency is the the specific
52:56brain substrates.
52:57So in the rodent models the lion's
53:00share the lion's share of the
53:02findings were hippocampal based in,
53:04at least in our hands.
53:05We we did not.
53:06We did not see the effects
53:08and that the campus.
53:11But I you know I, I don't.
53:13I don't know that, UM,
53:15we should expect to see sort of a
53:17one to one correspondence in terms
53:19of in terms of neural substrates.
53:22You know, I think the fact that
53:25analogous brain circuits are
53:27involved is probably enough to
53:30motivate further work in humans. And
53:33what about babies to adults is like
53:36the insular amygdala and a kind of
53:38depressive neural phenotype in adults.
53:41Yeah, for sure, and I'm sorry that I
53:44I didn't mention that so alterations
53:47in connectivity between the amygdala
53:50and insula have been implicated
53:53in anxiety disorders in adults,
53:56and have also been implicated
53:58in trait levels of anxiety.
54:00So not just the disorder per say,
54:03it's more implicated in
54:05anxiety than depression,
54:06but I think probably trying to
54:09parse anxiety from depression.
54:11Particularly at that early stage,
54:14it may be asking too much of the data.
54:17Thank you. Other
54:19questions, either in the
54:20room or in cyberspace.
54:27I'll explain my position
54:29and then I'm also curious,
54:30given that kind of breath.
54:32I guess you describe it as kind of civic,
54:35but the the breadth of
54:36disruptions that you see.
54:37It's interesting to me that you
54:39the epidemiological effects you see
54:41are really specific to depression,
54:44which I guess isn't really a question,
54:45but that's just some striking to me.
54:48It is it is striking, yeah.
54:52And and it is striking.
54:54And all honestly,
54:55I don't quite know what to make of that.
54:58I I certainly would have
54:59predicted that if there were,
55:01in effect on depression, you would
55:03also see that affecting on anxiety II.
55:06Suppose one possibility for that is
55:09that the anxiety effects were elevated,
55:13they just weren't elevated above
55:15and beyond the other groups.
55:17So it it may be that the because the.
55:22The prenatal maternal illness
55:24is also increasing anxiety.
55:27We're not seeing a differential effect.
55:30And for whatever reason,
55:32that differential effect is
55:34only located in depression in,
55:36you know, I realize that's not
55:37a very satisfying answer, but.
55:40If others have thoughts on that,
55:42I would I would love to hear your your views.
55:46I'm less good at Andres than making
55:48vague threats to people on zoom
55:51who aren't and drink questions,
55:52and we've gotten in vivo question.
55:56But we've got to run the mic to you,
55:59OK.
56:17Can you on me? Yeah, can someone on the
56:20zoom give me a thumbs up if you can hear me
56:22Linda or Faye? Yes, I can hear you.
56:25I can hear you well understood you well
56:28and we can hear you as well.
56:29So that's good.
56:30Hold on one second.
56:30We have a question.
56:31It just say your name.
56:34Hi, I'm Cassie.
56:35I'm a postdoc or post graduate trainee.
56:38UM and I've had two.
56:41There's sort of half baked questions,
56:42but one of the things I was thinking
56:45about is I was wondering like what
56:47kinds of sort of subjective self
56:49report information you might be
56:50getting from others during their
56:52pregnancies and thinking about like.
56:54What kind of I guess I've met anxiety they
56:56might be having about being on an SSRI
56:59and potential developmental effects if
57:01these are women who are of High SC accident.
57:05I don't know, just like putting
57:07myself in that potential situation,
57:09I could imagine not only
57:11be anxious in general,
57:12but like having anxiety about my anxiety
57:14and knowing that that might have an
57:16effect on my child's development.
57:17So I was curious about what kinds
57:19of subjective self report stuff
57:21you might be getting from moms,
57:23and then honestly,
57:24my seeking questions is keeping me so.
57:26I guess I'll just leave it at that.
57:29Yeah,
57:29I, I think it's I think it's a really,
57:31really great question and I and
57:33I I think that also you know it
57:35speaks it Harkins back to this
57:36issue of confounding by indication.
57:38So you know, if you have a a group
57:40of women who are depressed and not
57:42taking necessary versus a group
57:44of women who are depressed and
57:46taking this try is there some?
57:47Is there some reason for that?
57:48Is there some reason why one
57:51group was prescribed and SSRI?
57:53And uhm. You know,
57:56really definitively answering
57:58that is is really difficult.
58:01You know our our approach was to
58:04enroll early on pregnancy so we
58:07could start assessing from the get go
58:11throughout the course of pregnancy
58:12and then to assess quite frequently,
58:15so we'd have multiple data points so we
58:17could look at things like trajectories.
58:19You know,
58:20changing the depression symptoms overtime.
58:23Uh, the differences across
58:25various trimesters,
58:27which which likely have an
58:29effect on on fetal development.
58:32The the the cost in doing that in
58:35doing this very frequent assessments
58:37is that our we didn't want to send
58:42women no extensive questionnaires
58:43every two weeks to fill out.
58:45We just didn't think that would be feasible.
58:47That people understandably would get
58:49frustrated and stop completing them.
58:51So our our assessments are are somewhat
58:53cursory and that we're using that.
58:55The PHQ 9 and GAD,
58:59which is a I can't remember a
59:00seven or nine item questionnaire.
59:03Self Report questionnaire about anxiety.
59:05And then we're also assessing
59:07any substance use,
59:08so we're assessing frequently
59:10over a long period of time,
59:12but the type of granularity that
59:15you're talking about in terms
59:17of the nature of the.
59:19Anxious feelings I think it's going to be.
59:21It's going to be difficult to to tease apart,
59:24but I I think you I think you
59:25raised a great point.
59:29Thanks Jonathan and we have
59:30a question from Malia.
59:31Hi, thank you so much for
59:33this great presentation.
59:33Such important work
59:35as we try to tease apart all day,
59:38probably some outcomes.
59:40And I'm really excited to see
59:42your your longitudinal findings,
59:44because my understanding at least,
59:46is that sometimes you know
59:48cross sectionally and infancy.
59:49You may see some of these changes, but later
59:51on the differences are not
59:53significant any longer, so I'm
59:56curious if you could comment a little
59:57bit about that
59:58and and additionally I was wondering in
01:00:01your studies or other studies that you know
01:00:06about or you present
01:00:07it if of course, not with mice,
01:00:10but with with. Humans.
01:00:14How do you also control for other
01:00:17therapies that a lot of these
01:00:19mothers may be exposed to
01:00:21and thinking about the fact that
01:00:23some of these non pharmacologic
01:00:27treatments also have effects on
01:00:29brain morphology and connectivity?
01:00:32Yeah, you know, I think that the both really,
01:00:35really great question.
01:00:36So the first question about
01:00:38sort of the post Natal effect I.
01:00:40I think that is hugely important and you
01:00:44know, in a human longitudinal study.
01:00:48It's you know, the postnatal
01:00:50environment is really complicated,
01:00:51and so to be able to assess
01:00:53every aspect of it.
01:00:54Of course it's not not feasible, but we are.
01:00:58We're trying to really
01:01:00get a comprehensive view,
01:01:01and so the strategy that we're taking is
01:01:05that they'll be four post Natal visits.
01:01:08Two of them will be in the home
01:01:09where will have researchers go and
01:01:11actually assess the home environment,
01:01:13and two of them will be in the in the lab.
01:01:17There were quite, uhm, we.
01:01:21We think that's very,
01:01:22very important to have a good
01:01:23characterization of the parent
01:01:25infant interactions.
01:01:25So we're actually collaborating
01:01:27with accident investigator,
01:01:29who I believe has an affiliation with Yale.
01:01:32Ruth Feldman,
01:01:33who developed a coding scheme to
01:01:36to code parent interactions and
01:01:38will be assessing those at anywhere
01:01:41from two to three time points,
01:01:44will also continue to assess the the mothers.
01:01:48For for psychiatric symptoms,
01:01:51postnatally so postpartum depression
01:01:53anxiety and we are also this is
01:01:56going to be more of a challenge,
01:01:58but our goal is to also incorporate
01:02:00fathers into that assessment to be
01:02:02able to assess psychiatric symptoms and
01:02:04substance use in the father's as well.
01:02:08You know, I I. I, I think that we're
01:02:12doing our darndest to get a good
01:02:14characterization of the postman environment,
01:02:16but I I fully acknowledge that there's,
01:02:19you know, the environment complicated,
01:02:20and there's there's a.
01:02:21There's a limit to what we
01:02:23could do in that regard.
01:02:24But I I agree with your point.
01:02:26That's it. Very well could be the
01:02:29case that there are initial post
01:02:31Natal effects that are fully moderated
01:02:34by the the post Natal environment.
01:02:37Uhm? And your second question.
01:02:40Other other treatments?
01:02:41Yeah, I think that's I think that's a
01:02:44great point in our our short book study.
01:02:47We will have information about
01:02:49other treatments.
01:02:51It won't be as granular as I might
01:02:54like it to be, so we'll know if,
01:02:56for example,
01:02:57if a pregnant woman received
01:02:59psychotherapy for depression,
01:03:01but will have limited information about
01:03:03the nature of that psychotherapy and
01:03:06the duration of that psychotherapy
01:03:08in Sherbrooke.
01:03:09The access to psychotherapy
01:03:11is relatively limited,
01:03:12so we we don't think that's
01:03:14going to be particularly common,
01:03:15but certainly could be there
01:03:18another way to look at that is.
01:03:21You arguably there could be a direct
01:03:24effect of the psychotherapy on the fetus,
01:03:27but I think more likely it would be
01:03:29an indirect effect through the mother
01:03:31psychiatric symptoms, and so we will be.
01:03:33We will be capturing us.
01:03:36And we have one last
01:03:38question from the audience.
01:03:42Thank you Jonathan.
01:03:43Loved your talk. Just wonderful.
01:03:44The question is in terms of getting a
01:03:48cause and the impact of SSRI exposure.
01:03:51I'm wondering do you have any more
01:03:53granular data or senior Sherbrooke study
01:03:56in terms of the dosages
01:03:58that the moms are getting?
01:04:00Or maybe the
01:04:01timing of the doses that might be able
01:04:04to tell a little bit more about costs.
01:04:07Yeah, absolutely so.
01:04:09So timing, I think it's going to be
01:04:11hard to to get at a. We will have.
01:04:14We will have access to the medical
01:04:16records and the pharmacy records
01:04:18so we'll know what's prescribed.
01:04:20Although the dose prescribed and
01:04:22we'll know what's what was filled.
01:04:25Uhm, and so we can we can,
01:04:28you know from that we can calculate
01:04:31the net exposure.
01:04:32Will know if the doctor prescribed
01:04:34it for morning intake versus
01:04:36evening and take the extent to which
01:04:38the patient follows that advice.
01:04:40We won't be able to determine that.
01:04:44You know another thing that
01:04:45I I should mention,
01:04:46which is somewhat tangential and
01:04:48that's why I didn't bring it up
01:04:51before is that we will also have
01:04:53very a very extensive biorepository,
01:04:57so act deliberately delivery will
01:04:59be collecting placenta cord.
01:05:02Blood during pregnancy will have
01:05:04maternal blood, which if we wanted to,
01:05:06for example,
01:05:06we could test for SSRI levels
01:05:08in the maternal blood.
01:05:09It would be one snapshot,
01:05:11but it would be at least some
01:05:13quantification of of level.
01:05:14Uhm, and then we'll also be looking at,
01:05:17UM, some post Natal biospecimens as well.
01:05:19Things like breast milk and and how
01:05:22there are potential transmissions there.
01:05:27Alright, perfect timing and that
01:05:29we're at the top of the hour
01:05:30so everybody can hear actually stand
01:05:32up and walk like the old days work.
01:05:34Just click, leave meeting and
01:05:35then enter your next meeting.
01:05:37But Jonathan, thank you very
01:05:39much for spending your party afternoon with
01:05:41us as an outstanding talk and
01:05:42it's clear from the questions
01:05:44everybody found it enjoyable,
01:05:45engaging, so and personally it's
01:05:46nice to see you and I'll look
01:05:48forward to seeing you as a real 3
01:05:50dimensional movie sometime soon.
01:05:52Wonderful, thank you so much.
01:05:53Really a pleasure.