Yale Psychiatry Grand Rounds: "Recent Progress in Interventional Psychiatry"

January 26, 2024

"Recent Progress in Interventional Psychiatry"

Speaker: Samuel Wilkinson, MD, Assistant Professor of Psychiatry, Yale School of Medicine; Associate Director, Yale Depression Research Program

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00:00A generous introduction I I thanks
00:04for the plug about my family as well.
00:07I couple years ago I was asked to give
00:11a a talk to new faculty or something
00:14about how to be successful in research.
00:16And I I remember telling my family
00:18over dinner the night before and
00:19I was asked to give this talking
00:20about my son looked at me and said
00:22why are you asked to give this?
00:23You're not successful.
00:24So I I think it'd be good for you
00:26and him to get together and maybe
00:28he can convince you that your
00:30introduction was way too over the top.
00:32But that's all right.
00:34So can you.
00:35Let's see, are we doing this right?
00:37Can you see?
00:41Is this the right one? All right.
00:42Hopefully people can hear me.
00:45So as Jerry mentioned, I after I gave
00:49my the title of my talk to Trisha,
00:53I I shifted a little bit and said
00:54I wanted to focus on really the
00:56suicide prevention aspects of it.
00:57So the title might be a little bit
01:00not as accurate as it could be.
01:01I I apologize, but we'll talk a lot
01:04about interventional psychiatry.
01:05Here are my disclosures.
01:06I get funding from a variety of sources.
01:09I'll note that Yale has an institutional
01:11conflict of interest with S ketamine.
01:13I'll be speaking about that.
01:14That is FDA approved for for two conditions.
01:18What that means,
01:19the institutional conflict of interest
01:21basically is that Yale owns part of
01:22the patent for this and I'm employed
01:24by Yale that really above that.
01:27All of us have that institutional
01:28conflict of interest.
01:29But I probably talked about esketamine more
01:32than than most people in the department.
01:34So here's my outline.
01:35I'm going to be talking about making
01:38progress in suicide prevention research
01:39and there's two ways that our program
01:42has tried to approach this and one
01:44is through large data analytics and
01:46the other should clinical trials.
01:47And so just to expand this outline,
01:51I'll be talking about mainly
01:524 projects that we have either
01:55recently completed or are ongoing
01:57and why are we focusing on this.
02:01Many may know but but some.
02:03This may be somewhat of a of new
02:06information but this is a little
02:09bit dated but since 2000 really
02:12there has been a surge in in suicide
02:15deaths in the United States.
02:17This this stops in 2016 but if it
02:20if it extends you would see that it
02:22continues to go up and this is the
02:25overall number of deaths at this
02:27point it's around it's close to
02:2950,000 deaths per year by suicide
02:32which is just a terrible terrible
02:34thing and the rates are going up
02:37as well population adjusted rates.
02:39Males die by suicide at A at a greater
02:43rate than than females and a lot of
02:46you know this some of the major risk factors.
02:49This is not an exhaustive list but
02:51one of the one of the key risk factors
02:54that in the field we often allude
02:56to is that prior non fatal attempts.
02:58So if someone has attempted suicide
03:00before that is one of the key enduring
03:04risk factors for for death by suicide
03:06in the future for social support,
03:09older age, substance use and mental illness.
03:12One of the things that we that I
03:14think we may be under value or under
03:17appreciate and that could help us as
03:20we design studies is this risk factor
03:23of recent psychiatric hospitalization.
03:24And I'll talk a little bit about that,
03:27but just to put this into context,
03:29you know there's this is again
03:31also not an exhaustive list.
03:33Efforts at suicide prevention can
03:34focus on many different areas
03:36identifying risk at risk,
03:37individuals treatment means restrictions
03:38which is mostly getting rid of
03:41guns, but not entirely that.
03:43I'm going to be focusing on this
03:46second point here in treatment
03:48development and and implementation.
03:51So again these are the the major
03:54methods we're using to try to
03:56approach this problem and and
03:58and make progress in this area.
04:00So the first thing I want to talk
04:02about is related to ECT and suicide.
04:05A lot of people know what ECT is.
04:06Just as a brief overview for
04:08those who may be less familiar,
04:10it's a therapy for a fractory illness,
04:13most commonly depression.
04:14It involves passing electrical current to
04:16stimulate a seizure in a controlled setting,
04:19and the seizure usually lasts
04:20less than a minute or two.
04:22And these days anesthesia medicine
04:24prevents the vast majority of
04:26convulsion intensity such that
04:27the risk of orthopaedic injury
04:29is essentially 0 and a lot has
04:32changed since 1938 but it still
04:34does carry a kind of a a troubled
04:37history and and public perception.
04:39So why ECT for suicide.
04:41When I was a resident I remember being
04:44taught that there are two treatments
04:46that have consistently been shown at
04:48least two pharmacologic treatments that
04:50have consistently been shown to reduce
04:52suicide that's lithium and clozapine.
04:54And so I I remember doing some some
04:57research with this we Michael Block's
04:59group and and our group and and some
05:02others published a meta analysis looking
05:05at aside from antidepressants what's
05:07the relationship between pharmacologic
05:09and and somatic approaches on suicide
05:12and and ECT was kind of on the
05:15bubble the arbitrary P value point
05:17O five was not quite achieved but
05:20you see here the composite the green
05:25diamond showing potentially signal
05:27that the EC TS associated with lower
05:30lower suicide risk in in patients.
05:32But a lot of these studies are older
05:34they have some limitations in terms of
05:37the methodologies they're smaller and so.
05:42So I I was interested in trying to do
05:45a a more methodologically sophisticated
05:47modern study looking at ECT and suicide.
05:51So this was a,
05:53this was actually like first federal
05:55award is an R21 and it it allowed us to
06:00to acquire data from Medicare claims.
06:03We we focused on older Medicare patients.
06:07There's two ways you can get Medicare in
06:09in the US One is if you're 65 and older,
06:12the other is if you have a disability
06:15and any any way a patient touches
06:19the healthcare system,
06:21this we would be able to see that
06:22in this Medicare claims database.
06:24And we are,
06:25we're fortunate to be able to link
06:27this at the patient level to what's
06:29called the National Death Index,
06:30which is the most authoritative
06:33database of death in the United States.
06:35So we were designing an observational
06:38study and this is basically the P,
06:41the,
06:41the,
06:42the cohort that we're focusing on
06:4465 and older,
06:45we wanted them to have at least
06:47a history of hospitalization
06:48in the last year at least once.
06:51And of course, if they receive ECT,
06:53they they would be,
06:55if they're in the ECT group,
06:56they they need to receive
06:59at least one ECT treatment.
07:01Let me talk just briefly
07:02about observational studies.
07:03So there's this concept of index date,
07:06which is the period at AT AT which
07:07you start to measure the outcome.
07:09And that's a really critical concept to
07:12reduce bias in observational studies.
07:16And if you're comparing two groups,
07:17as you often are an observational analysis,
07:20you want the index state to represent
07:22a comparable point in time.
07:23So something significant is going
07:25on in Group one at the index state.
07:27You want something comparably
07:28significant to be happening in Group 2.
07:30So for this reason we chose the psychiatric
07:35hospitalization as the as the index state,
07:37More specifically the discharge from
07:39psychiatric hospitalization because
07:40when someone gets hospitalized
07:42obviously something things are
07:43not going well in their life,
07:46they're having a a crisis period
07:48and they need intervention.
07:50So this made sense as as the Enoch
07:53state and what we did here is in
07:56the again we have these two groups,
07:58the ECT group and the the non
08:00ECT group and we exact matched on
08:03basically as many variables as we
08:05could that had as much relevance
08:07as as we judged as possible on on
08:10suicide outcomes and we adjusted
08:12for for the variables we couldn't.
08:14We made adjustments through other methods.
08:18So you see here we get we have large groups,
08:2110,000 in ECT Group,
08:22A little over 30,000 non ECT group.
08:24And we're looking again,
08:26our main outcomes are suicide and
08:28all 'cause mortality and we look
08:31throughout up to a 12 month period
08:34and our data suggested at least
08:37for all 'cause mortality,
08:40ECG was associated with a substantial
08:41reduction in all 'cause mortality.
08:43This is a hazard ratio of about .6,
08:45which indicates a reduction in
08:47about 40% risk in all 'cause
08:50mortality among older individuals.
08:52And one of the things that you you
08:56are concerned about with observational
08:58data is of course confounding
09:00because these this is not randomized.
09:03So individual doctors make decisions
09:05based on information much of which
09:08might not be in the database.
09:10So one of the ways we're trying to
09:12get at this is by looking at those
09:15who had what we defined as a sub
09:17therapeutic course of ECT and as
09:19you see which we define as less
09:21than five ECT treatments.
09:23And as you see here those who had
09:26a sub therapeutic course at least
09:27for the first six months or so
09:29their mortality outcomes track.
09:30Those who didn't get any ECT suggesting
09:34that this is not all confounding that
09:36I think there is some confounding here
09:38but it it doesn't explain explain away
09:41that the whole potential treatment effect.
09:43So this is a a pretty big effect
09:46especially with with mortality which
09:49was encouraging ECT.
09:50Excuse me?
09:51Suicide is an outcome.
09:52It's a little more complicated.
09:54These these are the the panels on on
09:57suicide deaths and and for the first
09:59six months or so you may see a little
10:01bit of a separation but that seems
10:04to go away after after six months.
10:08This is a a different way of
10:11showing essentially the same data.
10:13So the the top half of the panels
10:15look at all 'cause mortality and the
10:17bottom half look at suicide, death.
10:20And you see the the all 'cause
10:22mortality for all times points
10:24is associated with lower,
10:26lower risk of death in the ECT group.
10:29And the suicide,
10:29at least for the first three months or so,
10:32there is an association,
10:34significant association,
10:35but that tends to wane over time.
10:38And so you know,
10:41interestingly,
10:41we were not the first group to do this.
10:43There were actually three or four
10:45other groups that pick this,
10:47pick this issue up at the same time
10:49and published in other databases,
10:52essentially a very similar
10:54analysis such that we're revising
10:56and updating our meta analysis.
10:58This is this is not not yet
11:00published we're preparing this
11:01still but you see here a number of
11:05studies more recently in 2021-2022,
11:082020 of much,
11:09much larger sample sizes and they
11:12are converging at least with the
11:15mortality outcome that that there
11:17is a a a fairly large association of
11:21reduction in mortality associated with ECT.
11:25So I I think that's pretty cool.
11:28The suicide again it's it's
11:30a more complicated picture.
11:31Not all the studies report outcomes
11:33at the at the same time points
11:35but as much as they do or we could
11:37get a little bit of a sense.
11:38There seems to be at least in these
11:40first few months potentially in
11:42association with a reduction in suicide risk,
11:45suicide, death risk.
11:46But unfortunately that tends to fade
11:49the further out you get from from
11:52the beginning of of the study. So
11:56you know the the key take away I
11:58would say I would I would have I'm
12:00pretty convinced that that ECT can
12:01reduce all 'cause mortality and this
12:03is seen across several different
12:06studies including those higher
12:09quality more sophisticated more
12:12sophisticated methodologies and and
12:14modern studies ECT mainly to reduction
12:17in suicide in the first six months
12:19but effects seem to diminish over time.
12:22The unfortunately the data is not
12:26not grainy enough to from for me
12:28at least for us at least at this
12:30point to determine whether that has
12:32to do with the fact that a lot of
12:33people don't get maintenance ECT
12:36and and relapses after ECT without
12:39maintenance can be can be high in
12:43terms of trying to figure out how we
12:45can make this therapy more available.
12:47Because ECT is only available in
12:49about 10% of psychiatric hospitals,
12:51we we did try to do a a naturally
12:55national survey and we we were
12:57fortunate to get about about 1/4
12:59to 1/3 of all those who do ECT.
13:02There's about 800 docs in the US who
13:04do ECT to tell us what they think.
13:06They're the most prominent barriers to
13:09either expanding an existing service
13:11or starting a new service And here you
13:14see the three most at least reported
13:16problems and and that's lack of
13:18physical space stigma and transportation.
13:21When you ask what is a barrier to
13:23expanding an existing service you
13:25get lack of space is #3 and then
13:27lack of well trained colleagues or
13:29a champion And if I were to you
13:31know if I had a lot of power and
13:33decision making authority what I
13:35would say are the two things that
13:37can most be done to make ECT more
13:39readily available because it's it's
13:41it's not readily available it's not
13:44uniformly available it's very patchy.
13:46One would be to adjust the A/C,
13:49GME requirement for psychiatric residencies.
13:53Right now the the requirement is essentially
13:57to to just have exposure to ECT.
13:58It can be even be just in a lecture
14:02and you know if you think well in
14:05cardiology if all they had to do was
14:07to learn about cardiac catheterization
14:09which is one of the most effective
14:12procedures that probably wouldn't
14:13make a lot of sense.
14:14But this is this is how it is in
14:17psychiatry And if you know this was
14:18bolstered by the the finding that
14:20about a third of our ECT respondents
14:22in in in that survey had graduated
14:25from just one of 12 residency programs
14:28who were who had robust ECT services.
14:30And just to give you a sense there's
14:32about 350 today there's about 350
14:35psych residency programs and twelve
14:37of those led to at least of the
14:39people who responded to our survey,
14:41about a third of our survey respondents.
14:43The others to allow ECT to be
14:45done in non hospital settings.
14:46This is a federal government issue.
14:48This is with CMS that typically
14:50does not reimburse ECT if it's
14:52not in a hospital setting.
14:55And this you know we're competing against
14:59other procedures like gastroenterology,
15:00cardiology that sort of thing.
15:03And unfortunately because of
15:04the way reimbursement works,
15:06we're often you know the 1st to kind of
15:08be pushed out or or not have the space
15:11that we need to to do these things.
15:13And if you could make it so that ECT
15:15be could be done in in ambulatory
15:18surgical centers and so
15:19forth, this would make it a little
15:22more a little easier to to have the
15:26space that that this service needs
15:28to to to to be able to to to operate.
15:32So that's that's all I'm going
15:33to say about ECT.
15:34You know hopefully these these
15:36findings can be of interest in and
15:38help this become more available.
15:40I want to shift a little bit and
15:41talk about intensive outpatient
15:43programs and and suicide.
15:44This is a A the project that we are
15:47just getting underway now and this
15:50this idea in part was compelled
15:53by this finding and this was put
15:56well by some rabble rousing second
16:00year residents from this is almost
16:0330 years ago but they they were
16:05rotating in the child service.
16:07This was during a time when the
16:09average length of stay in the
16:12hospitals was reducing drastically.
16:13And a lot of the staff at this
16:14time were upset.
16:15And the residents asked, well,
16:16you know, what is the evidence that a
16:18longer length of stay is more beneficial?
16:20And they were told, well, it's actually,
16:21there's not a lot of evidence,
16:23but we think it's helpful.
16:25And you know this,
16:27this was actually Jerry was among
16:29these these residents who who voiced
16:31this problem and concern of you know,
16:33kind of lack of evidence of a lot of the
16:36things we do in psychiatry and you know,
16:38intensive outpatient programs.
16:39It really started to proliferate around
16:42this time in the mid 90s when managed
16:44care started to become more common
16:46and the length of hospitalization
16:48dropped quite significantly.
16:49And it's these,
16:50these were instituted as a way
16:53to manage high risk patients who
16:55no longer met the kind of the new
16:57criteria for hospitalization and IO.
16:59PS were of course much less
17:03expensive than hospitalization.
17:04But again this wasn't,
17:05this wasn't something where people said,
17:07OK, we've designed this treatment,
17:09it works really well. We've tested it.
17:10So let's implement it.
17:12It was more you know the financial
17:14expedience of of the way healthcare works.
17:17What is IOP IT it generally consists
17:20of somewhere between 12 and 20 hours
17:22per week of of patient interaction,
17:25most in the form of group therapy
17:28generally time limited to maybe two
17:30to three months and it is often
17:32used for high risk patients leaving
17:34the hospital or as an alternative
17:36to hospitalization.
17:37One thing I should note about it
17:39however is that it's not uniformly
17:40distributed.
17:41I don't think it's quite as bad as ECT.
17:43We're only 10% of psych hospitals
17:46provide ECT.
17:47But I would say roughly half of the country,
17:50you know in some states these
17:52these things really don't exist.
17:53Whereas in in New Haven as a rough estimate,
17:57I would say 30 to 50% of patients that
18:00leave YPH leave the inpatient units
18:04on Y pH intensive outpatient programs
18:06are a key part of their discharge plan.
18:09So again there's this uneven distribution
18:11of these these programs and these
18:14services throughout the country.
18:16So I we our program, we wanted to study
18:21in a sophisticated way what is the
18:24evidence for them in terms of suicide
18:26risk reduction and we we want to focus
18:29on the period following hospitalization.
18:32One of the reasons is because as
18:35I mentioned earlier in the talk,
18:37the period following discharge is one
18:39of immensely high risk for suicide.
18:42It's most acute in the first three months.
18:44It does come down somewhat after that,
18:48but you know it's it's just an extraordinary
18:52high risk just to give you some numbers.
18:55So the usually suicide rates are measured
18:57in per 100,000 person years and the base
19:00rate for general population is around this.
19:03This paper indicates 11.4.
19:04It's a little bit higher these days
19:05unfortunately because the rate has gone up,
19:07but it's it's around 12 to 13 if
19:10you look at it someone who comes
19:12into the hospital suicidal,
19:13their rate of suicide risk in the
19:16falling hospitalization is 2000.
19:17So 2000 compared to you know 12
19:21or 12 or 13 events per 100,000 is
19:24it's just a huge increase in risk.
19:28So in a similar way to the way
19:30we conducted the the ECT survey,
19:32excuse me project looking at
19:36at risk reduction of suicide,
19:38we are looking at intensive outpatient
19:41programs or partial hospitalization programs.
19:43There's a difference,
19:44but it's it's it's subtle compared
19:47to non intensive outpatient care
19:49following psychiatric hospitalization
19:51and we are going to do this in,
19:55in the Medicaid population.
19:57And again we're just getting
19:59this project underway,
20:01but hopefully in the next two years or so
20:04we'll have some interesting results and
20:06you know the strength of this project,
20:08what we'll have very large sample sizes
20:11estimated about 100,000 per group.
20:13Another strength is that this in my opinion,
20:16this could be leveraged and
20:18implemented relatively easily.
20:19If we find that IO PS actually reduce
20:22suicide in post hospital discharge period,
20:26these exist in about half the country
20:28and could we therefore make them exist
20:30in the other half of the country?
20:32And you know,
20:33re make real progress in reducing
20:36the suicide rate as is one of
20:38the key goals of the NIH.
20:40Another strength is that it's focused on
20:42in a context of extraordinary high risk
20:45as as always the you know observational
20:48studies they they do have this weakness.
20:51There's confounding we have to really
20:53think about critically and then be
20:55based on the way claims data works
20:57which is the data we'll be using.
20:59The details of programs are limited.
21:02We will be,
21:03we do have a a perspective survey that
21:05will conduct as part of this project that
21:07will help us mitigate this weakness.
21:10So this is a a federally funded project
21:14that we're excited to get get off the
21:16ground that we're getting off the ground.
21:18Gregory is a Co Pi.
21:19He's a really extraordinary biostatistician
21:23who I've worked with over many years,
21:26primarily based at UConn.
21:27He has an adjunct appointment here.
21:29He's worked with many people
21:30in our department.
21:31Katie Cleaning Smith who's a a Co
21:33eye on this project and is the head
21:36of yells out P Services is also a
21:39key collaborate in this study and
21:41we we have a group of stakeholders
21:43who from various organizations who
21:45will hopefully be able to help us
21:48implement any actionable results
21:50that that this study finds.
21:52So that concludes my the portion
21:55I'm going to talk about large data
21:58analytics and and trying to move the
22:00needle and suicide prevention research.
22:02I am going to shift now a little bit
22:04and talk about some of the work that our
22:06our program is doing in in clinical trials.
22:08And I'm going to start with just some of
22:13the the background of this and limitations
22:16in in this space that have existed.
22:19And the fact is that most clinical trials,
22:20mental illness I've systematically excluded
22:22those at substantial risk of suicide.
22:25There's various reasons for that
22:26that I won't get into now but this
22:28of course is a big weakness in it
22:30and there's a huge limit of of data
22:33and how are treatments that we're
22:35using on a day-to-day basis affect
22:37people at risk of suicide.
22:39Fortunately at there is there are
22:41efforts that this may be there are
22:44indications this may be changing.
22:46There's a number of modern studies that
22:49are either ongoing or recently completed
22:52where trials are are specifically
22:55focusing on on those at risk of suicide.
22:59One of those studies that we're a
23:01part of right now is sponsored by
23:03we Therapeutics as a company that
23:06has a strong tie to the department.
23:08So Steve Bunny,
23:10Seth Fierstein and and Patricia
23:11Simon are are part of we and we
23:14are one one side of a multi site
23:17study that that they are running to
23:20evaluate a digital therapeutic in in
23:23reducing risk of suicide behavior.
23:26So this is a a traditional
23:30design AA1TO1 ratio,
23:31two group randomized trial where
23:33patients are randomized to an active
23:38group that has the the experimental app
23:41plus psychoeducation plus treatment as
23:43usual versus just the psychoeducation
23:45app plus treatment as usual.
23:47And the the primary outcome measure
23:50here is group difference in suicide
23:52behaviors as measured by the Columbia
23:55scale following discharge from a
23:57psychiatric facility for up to two years.
23:59The app is based on David Rudd's work
24:02using CBT to reduce suicide risk and
24:05veterans and it's a you know very,
24:08very respectable sample size of
24:10almost 400 participants that is
24:12the goal to to recruit.
24:14It's one thing that's interesting
24:15is this is transdiagnostic
24:19really the the the key inclusion
24:21criteria is that that you're
24:22admitted to a psychiatric facility
24:24because of suicidal ideation.
24:27We're going to exclude people who
24:29aren't going to be able to meaningfully
24:30participate in a in a in an app
24:32program or or something like that.
24:33But otherwise it's it's a very broad
24:35trial and it and it's transdiagnostic.
24:37So this is a specific trial that
24:40we're we're one of of several sites
24:42that are participating in this
24:44and I'm just going to use this to
24:47to do a slight tangent on why I'm
24:49excited about digital therapeutics.
24:50I know that the speaker next week probably
24:52has a lot more to say about this.
24:55Digital Therapeutics I think have
24:57a the potential to really rebalance
25:00the funding portfolio for for
25:02clinical trials and I'll share a
25:03little bit what I mean.
25:04So Para Therapeutics,
25:05I don't have any ties with this
25:08company by the way they they were
25:10the first to really be able to push
25:12through the FDA a an app that it was
25:16designed to help people with substance
25:18use disorder engage in in CBT type
25:21principles and adopt CBT type principles.
25:23So,
25:23so why am I excited,
25:25why do,
25:25why do I think this makes this has
25:27a lot of potential to solve some
25:29of the problems our field has and
25:31one of the reasons is because you
25:33know the vast majority of research
25:34funding comes from industry.
25:35This is the just a picture of the
25:38the imbalance between industry
25:40funding versus NIH funding and the
25:41vast majority of industry funding
25:43is in clinical trials.
25:44But up to this point the industry has
25:46had no really reason or incentive to
25:49get involved in psychotherapy research.
25:51And you know digital therapeutics
25:53are not necessarily psychotherapy,
25:54but they're psychotherapy like.
25:56And so this has the potential to
26:00draw in interest from industry and
26:03and funding from industry to really
26:08fund large clinical trials and of
26:12of psychotherapy like approaches
26:14through digital therapeutics.
26:16Another big problem is that
26:19these things can help us improve
26:21implementation of therapies.
26:21We've known for a long,
26:22long time that cognitive behavioral therapy
26:24is a is a very evidence based treatment,
26:26but it's really hard to get in the community.
26:27It's really hard to find a good
26:29therapist who who sticks to
26:31the model and and you know,
26:33assigns homework,
26:34sets an agenda and so forth.
26:36And and digital therapies can help
26:38solve that problem as well.
26:39So I'm excited about the way that
26:42this could help transform psychiatry
26:44to drawing a lot more funding from
26:48industry to develop psych therapy
26:50like approaches as well as to help
26:53implement those that are shown
26:55to be effective.
26:57So that's all I'm going to say
26:58about digital therapeutics.
26:59Let me shift a little bit to
27:03esketamine which many of you may know
27:06was approved almost five years ago.
27:09It's crazy how time flies,
27:10but it was approved initially for
27:14TRD treatment resistant depression
27:16following some FDA registered studies,
27:19some key trials for patients with
27:22depression and suicidal ideation.
27:24It also had a supplemental
27:27indication that it's approved for
27:29depression with suicidal indication.
27:31This was the phase two study.
27:34The the Yale Depression Research
27:36Program participated in this.
27:37The primary outcome here
27:39was a 24 hours post dose.
27:41So it wasn't you know necessarily at
27:43every time point there was a there was
27:45a difference but but it was enough
27:48to to lead to phase three studies.
27:51These were called the ASPIRE studies
27:53of about 220 or 30 patients each
27:57randomized to every patient got
27:59good standard of care including
28:01hospitalization and then half of them
28:03got it as ketamine plus standard of
28:05care and haven't got placebo plus
28:07standard of care plus a new antidepressant.
28:09Every patient got a new antidepressant.
28:11So this was enough data for the FDA
28:15to say OK, we are going to prove this,
28:17this treatment for depression with suicidal.
28:21I do want to just note here some of
28:23the adverse effects of esketamine
28:25either straight from the FDA label.
28:27The vast majority of these,
28:28maybe with the exception of headache,
28:30are limited to the one or one hour
28:32or so where patients are in the
28:35experiencing the acute effects of escetamine.
28:37Headaches often happen later that
28:39day or maybe the next day kind of.
28:42At most.
28:43Escetamine does have a boxed
28:45warning of sedation,
28:46dissociation,
28:47abuse and misuse and suicidal thoughts
28:49and behavior.
28:50I will note that the the risk for
28:52suicidal thoughts and behavior that is
28:54simply a carryover from antidepressant.
28:56The antidepressant box warning
28:59for were suicidal thoughts and
29:02behavior because that's going to
29:03be was designed to be started with
29:06initiation of a new antidepressant.
29:09So as I mentioned this led to the
29:11FDA approval of this medicine for
29:14depression or suicidal ideation
29:16what some folks call MDSI.
29:18One of the weaknesses we thought
29:20existed in this protocol was that
29:22treatment stops after four weeks
29:24that was has the how the studies were
29:26designed and based on the data we
29:30know that after you're hospitalized
29:31is really high risk period.
29:33One of the key concerns in the
29:35ketamine world at least initially
29:36and and still some to some degree
29:38is that you know if it if something
29:40is a rapid acting antidepressant,
29:42if you stop it can people rapidly
29:44relapse and that is definitely the case.
29:46And so are we setting people up for
29:49you know a really hard relapse and and
29:52potential you know high risk of of suicide.
29:56So based on our work where
29:58we've tried to combine ketamine,
30:00racimia,
30:01ketamine in prior studies with
30:03cognitive behavioral therapy
30:05suggesting that there may be some way
30:07to kind of combine these treatments
30:09in a in a synergistic way.
30:12We have designed a study to to combine
30:18S ketamine with CBT and in people people
30:24with depression and suicidalization.
30:25Originally this was intended to recruit
30:27only from the inpatient setting.
30:29We've since expanded it to enroll
30:31people from the outpatient setting
30:34who also have significant SI
30:36and we are we are running the study
30:39it's it's this is funded by a an RFA
30:41a large RFA that's funding a number
30:43of studies around the country but
30:45this this funds this study Yale is a
30:48primary of three sites and patients are
30:51all patients get esketamine patients
30:54with depression and suicidal ideation
30:56half of them will receive CBT that
30:59starts about two weeks after they
31:02they begin esketamine and and patients
31:05are followed for up to six months.
31:07So our target enrollment is is 100.
31:09We should be wrapping up the study
31:11at the end of this year.
31:12We are about 2/3 the way through with
31:15with recruitment and again Yale is the
31:18primary site of of a a three site group.
31:20Emery and Alabama are also participating.
31:25So that is the what we're calling the
31:28CBT endure study to try and again make
31:32progress in in in suicide prevention.
31:35So I want to come back again to
31:39what what at least I have learned.
31:41I think we've learned in in the depression
31:43research program about how to conduct
31:46suicide prevention clinical trials
31:48and again with the context that most
31:50trials have excluded those at risk.
31:52There again have been I think
31:54indications that this this is changing
31:57the ASPIRE studies that led to
31:59Jansen's FDA approval of Escanamine
32:01for depression with suicidal iation.
32:03Those are some you know well funded studies.
32:06The ENDURE study is is part of a
32:09number of RF as from the NIH that
32:11are explicitly calling for trials
32:13to to focus on suicide prevention.
32:17There's a lithium trial that was based in
32:20the VA unfortunately that was negative.
32:21But again we need to do these studies.
32:24The WE trial I mentioned the SPOT trial
32:27from Greg Simon that was based in Kaiser.
32:29The Kaiser Healthcare system was one
32:33that focused on suicide prevention
32:34and clinical trials.
32:35So just a couple of the key takeaways
32:39for those of you who do clinical
32:41trials or in in other ways and you
32:43know one of the key issues is how
32:45to identify patients and and this
32:48is actually a a key problem for any
32:51clinical trial and mental illness.
32:52It it's it's so interesting whenever I
32:55talk about what I do with friends and
32:57family who are not in medicine and I
32:59mentioned that we do clinical trials
33:00for mental illness and one of the key
33:03problems is, is finding patients.
33:05You know that that doesn't seem
33:06to make sense.
33:07There are there's an abundance of
33:09people who are desperately seeking
33:11care but our systems haven't figured
33:13out a way to in a in a good way,
33:15an efficient way align trial recruitment
33:18with those who are are trying to seek help.
33:21But in in this case if we can recruit
33:25from Ed settings or hospitals,
33:27then that helps us I think with an
33:29enriched sample and it helps us
33:31because there's a steady flow of
33:33patients through these settings.
33:35And this relates to what I think
33:37is just critical
33:38if we're going to make progress in
33:40treatment development in mental
33:41illness generally is that we need to
33:43bring together clinical and research
33:45missions and academic centers.
33:46This is not an easy thing. There's a
33:48lot of structural impediment to this.
33:50But it I'm convinced that if
33:51we're going to make progress,
33:52this needs to happen.
33:53If we're going to run good
33:55quality clinical trials,
33:56this needs to happen not just
33:59for suicide prevention trials
34:01but for all all clinical trials.
34:03Another tricky thing about clinical
34:06trials with in suicide prevention is
34:08you can't tightly control treatment.
34:09So we think about RCT,
34:11it's randomized controlled trial.
34:12You control the treatments except
34:14for one that is randomized and
34:16thereby you can elicit causality.
34:18But in it's not ethical to do
34:20that with suicidal patients.
34:21And so the analysis generally needs
34:23to be a time to event and an event
34:26could be well the patient crumped
34:27and they need a new treatment,
34:29they need ECT or whatever could
34:31be hospitalization could be
34:32a composite of these things.
34:33The definition of the event is critical,
34:36but these things generally need
34:37to be time to event studies.
34:40And one thing I like about some
34:42of these studies, you know,
34:43they're focusing on outcomes
34:44that are meaningful to patients.
34:45So suicide behaviors, hospitalization,
34:47not just a rating scale,
34:49which are important but more
34:51meaningful to patients are do
34:53they have to get hospitalized?
34:55Do they act as their family member,
34:57actually attempt suicide?
35:00This is the direction we need to go.
35:02That's a high bar,
35:03but I think that's this is
35:05a direction we need to go.
35:07Another critical thing is a
35:08somewhat of a nuance,
35:10but standard of care needs to
35:12be the comparator arm.
35:13It can't just be placebo for ethical reasons.
35:16And there's a critical difference
35:18between standard of care and
35:19community versus research settings.
35:21And finally,
35:24in terms of regulatory issues,
35:25there needs to be a change in
35:27culture where we can't stop a study.
35:29If one, one event happens,
35:32these things are going to happen.
35:33It's it's terrible,
35:34but we can't stop oncology studies
35:36when someone dies of cancer.
35:38Likewise, if we're recruiting specifically
35:40patients who are at risk of suicide,
35:42we need to somehow change the
35:44culture that we can't stop a
35:47study just because of one event.
35:48Now if there's gross negligence or or
35:50things are not being done properly,
35:53obviously that's an issue.
35:54But these things unfortunately are
35:56going to happen and and if we're going
35:58to make progress we need to be able
36:00to to meaningfully conduct studies
36:02in these types of of populations.
36:05So, so that's what I'm going to say
36:08about our our work in suicide prevention.
36:10I will mention just one other study and
36:13and notably the many of these studies
36:15are conducted within the context of
36:17of interventional psychiatry service
36:19which is a collaboration between the
36:22university and the and the hospital.
36:25In in our interventional service there
36:28are three three key treatments that
36:30are offered to patients ECT Ketamine
36:33S ketamine TMS especially in the last
36:36five years with the FDA approval
36:37our ketamine S ketamine service,
36:39the volume has grown tremendously
36:41and you know there are a lot of
36:44interesting issues you know one of
36:46which you know with with the recent
36:48death and and really autopsy reported.
36:50Matthew Perry you know just really
36:52brings to the forefront one of these
36:54questions that that we get all the
36:56time in the in the ketamine world with
36:58whether there's a meaningful difference
37:00between ketamine and S ketamine.
37:03You know I I was shocked to read
37:05from the New York Times that the the
37:08coroner the medical examiner judge
37:11that ketamine played a contributing
37:13role to Matthew Perry's death.
37:15This brings to the the forefront of
37:17some of the challenges that we've
37:19been wrestling with again of this
37:21is there a meaningful difference
37:22between S ketamine and ketamine from
37:24a clinical perspective there's a
37:26lot of differences from a kind of
37:27a healthcare system perspective.
37:28S ketamine has FDA approval.
37:31IV ketamine does not have the FDA approval.
37:33S ketamine is subject to a very,
37:35very strict drug safety program.
37:37The REMS ketamine is kind of the wild,
37:40Wild West and there's a lot of
37:43things going on that that probably
37:46shouldn't be going on.
37:48Last year,
37:48this is the first I heard of it
37:50where the federal government stepped
37:52in and shut down a clinic of a,
37:56of a of a Doctor Who was,
37:58you know,
37:58sending ketamine for at home consumption,
38:01at home use.
38:02He had obtained licenses in most
38:04states across the US and you know,
38:07was treating something like thousands
38:09of patients and the DEA came in
38:11and and and and shut him down.
38:13So there's a lot of healthcare differences
38:16between S ketamine and ketamine,
38:17the way it's regulated and so forth.
38:19And there's confusion among patients,
38:21third party payers,
38:22providers in the general public.
38:24This is a quote from Glenn Brooks,
38:26who is probably one of the first
38:28to start a ketamine clinic in in
38:31Manhattan who says, you know, Ivy,
38:34ketamine is the gold standard.
38:35So we don't offer S ketamine.
38:36And there's a there's there's
38:38more opinions in the world,
38:40in the ketamine world about this than data.
38:42Fortunately we we recently received
38:45funding to try to settle this
38:47question and run a head to head
38:50study with you know respectable
38:52sample size where patients are
38:54randomized ketamine or S ketamine.
38:55We're likely going to call this
38:57the equivalence trial because it's
38:59acronym as it's one of the patient
39:01center outcomes research and we're
39:02excited to get get started with this.
39:04We hope to start enrollment in September.
39:07So I know this is kind of a
39:08whirlwind of of some of the stuff.
39:10Hopefully there was a an underlying
39:12theme through most of it.
39:13I just want to thank so many of the
39:15people who make this research possible
39:18in the depression research program as
39:20well as the interventional psychiatric
39:22service at Yale New Haven Health,
39:24some of my Biostats and EPI collaborators
39:27or other institutions and and
39:30increasingly you know in the in these
39:32these studies focused on suicide
39:34prevention the the emergency services,
39:36the psych emergency services.
39:38We're in there all the time and appreciate
39:40you helping us to facilitate the conduct
39:42of of of these important studies.
39:45So again thank you to the for your interest.
39:49Thanks so many of our collaborators in
39:51the in the depression research program
39:54and and interventional psychiatry and
39:57that is all I have for prepared remarks.
39:59So I think I'll stop sharing and.
40:01I think it's time for Q&amp;A.
40:03Is that right?