Transcript of
N.A.R.S.A.D.
NARSAD Webinar
April 10, 2010
Participants
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Herbert Pardes, M.D., President
Jeffrey A. Lieberman, M.D., Chair of Psychiatry
Sarah Holly Lisanby, Professor of Psychiatry, Columbia
Blair Simpson, Associate Professor of Psychiatry, Columbia
Presentation
Herbert Pardes, M.D. – NARSAD – President
Well, we’re happy, even if it’s a little late in welcoming everybody and I just want to put
this in context. My name is Herb Pardes and I am President of the Scientific Council
of NARSAD. And I imagine there are many people in the audience who have been
part of this family for some time but it’s a rather interesting one and had its origins to
some degree in a meeting that we had at Columbia in approximately 1985 I think it
was, about 25 years ago when Connie and Steve Lieber walked in and saw the
conference and it was an attempt to talk about research in psychiatric illness in plain
talk and Connie and Steve indicated they were interested in trying to be of some help.
Well that has, that little kind of coming together has led to an extraordinary
organization which now, over the last 20 or so years has given something in the
neighborhood of $256 million in grants to thousands of investigators across the
country and the world of all kinds of disciplinary stripes really focusing on the major
psychiatric illnesses. And the thing that has always plagued those of us in this field is
how broad the victimization of people is by scientific illness, in the conversation I had
with Jeff a little earlier, we were talking about the fact that the estimated rates of
prevalence of psychiatric illness around the country are anywhere from 19-25%.
So whatever, whether it’s 19 or 25, those are a lot of people and one of the things
that’s been important is getting people to come out and really work to help us find our
answer to the disease and NARSAD has been a key enterprise in making that
happen. I would say in psychiatric research, very few people these days who are in
psychiatric research have not been touched by NARSAD in some way or other
because NARSAD helps young people help people who are, who have been in the
field for a while and helps people who are distinguished. It also drives the draw of
very outstanding scientists in other fields to try to have as diversified and as
innovative a research program as possible. Now in that connection, the Lieber’s and
the NARSAD leadership came up with the idea of trying to spread the message
across the country and so Healthy Minds Across America is designed to do that and
you should know that this is one of 44 centers which will be featuring symposia on
psychiatric research and that a number of them will be viewed by a people nationally
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and so on the one hand we want this to be as good a symposium for you as possible
but also realize that we’re part of this national network.
Now I am very happy to include one other message and that is that one of the ways
that all of us can help is that NARSAD at the end of the day is still a private
organization which is supported by those of us who try to help providing it with the
necessary support. That money I mentioned came from fundraising and Steve and
Connie have set a target for us to dramatically increase the fundraising or the funds
for NARSAD and so I would encourage everybody, I don’t care if it’s a dollar, a penny,
whatever it is, it helps and if the large numbers of people do it and if we can reach the
numbers of people affected by psychiatric illness, there’d be tremendous support for
psychiatric research and we’re hoping that’s what will come out of it.
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I have the pleasure of being the Chair of Psychiatry here for about 16 years, some
time ago and then following me an outstanding Psychiatric Investigator took charge
and has done a magnificent job over the last several years, he is going to be our
moderator this afternoon. So it is my pleasure to introduce to you now, Dr. Jeffery
Lieberman who is the Lawrence C. Kolb Professor and Chairman of Psychiatry, the
Lieber Professor of Schizophrenia Research. Columbia and Psychiatric Institute have
a wonderful partnership which creates probably one of the strongest, if not the
strongest program in Psychiatric Research in the country and Jeff, leading that has
made it even stronger. It is my great pleasure now to introduce Dr. Jeffrey Lieberman.
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
Thank you Herb and good afternoon ladies and gentlemen. It’s really a pleasure to be
here even if it’s a Saturday afternoon and even if it’s a beautiful day outside because
we’re here to celebrate a wonderful thing. And that is, really the emergence of
biomedical research on the brain to investigate and understand the causes and
develop treatments and ultimately, the cures for brain disorders that reflect
themselves by disturbances in mental functions and behavior. And it wasn’t too long
ago that there was very little or relatively little known and not many people in the
general public or population were willing to talk about it openly. But that’s all changed
and it’s changed within a relatively short time, within my professional lifetime. And a
big reason that it has changed is because of the way biomedical research has moved
forward, psychiatry has taken advantage of that and most importantly organizations
like NARSAD have come into being and have become powerful forces in generating
resources to support this research enterprise. And I think it’s accurate to say that if it
wasn’t for organizations like NARSAD that we wouldn’t be where we are today and we
wouldn’t be facing the very bright and favorable prospects making rapid progress
about mental illness.
It’s really a debt of gratitude that I and the other investigators, the other faculty that
are going to speak to you today but I dare say that’s the case for virtually every
researcher in psychiatry across the country and they have had a long term association
throughout their career with NARSAD, getting funding for research at various stages
of their career so I want to stay thank you, I want to publicly acknowledge Connie and
Steve Lieber who have been really the guiding spirits, inspirational forces within
NARSAD and also we have today really an honored guest today, Ms. Bet Custer[ph]
who has been not just somebody who has been actively involved for many years with
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NARSAD but with the National Alliance for the Mentally Ill, in particularly in New York,
in New York City and New York State actively involved with the National Alliance for
the Mentally Ill, so good to see you here today Beth.
Well we have a fabulous program for you, it’s really kind of, you know you go into a
restaurant and you have a menu of a few simple things and you’re going to order a la
carte and figure what is it I’m going to have today and what we did was try to pick
some things that are representative of what is going on in the field in the various major
mental disorders. So what we’ve done is we picked today three of our faculty to talk
about different topics and when I say our faculty I’m talking about people that come
from the Columbia University New York State Psychiatric Institute, New York
Presbyterian Hospital faculty and just to explain what I mean by that, where you’re
sitting right now is in the ground floor, if we could have the lights down just a little bit
back there Brad, lights down. Don’t tell me our light switches are disabled also,
maybe Rachel you could go and just alert them in the back to put the lights down? So
we are in the ground floor of this building, the Parnus Building of the New York State
Psychiatric Institute, this is the Call Building of the New York State Psychiatric
Institute, this is Columbia University College of Physicians and Surgeons and this is
New York Presbyterian Hospital so our faculty really are part of all of these three
institutions which are joined through affiliation agreements.
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So to begin you’ve heard from Dr. Pardes. Unfortunately because of our technical
difficulties we’re not able to show the video, but we will begin with the program which
will begin with Holly Lisanby, who will be talking about brain stimulation in psychiatry.
You know, treatments in psychiatry prior to 1950 were practically nonexistent. They
were largely just custodial care and trying to support people in human fashion but now
we have three modalities. We have the talk therapies, psychotherapies; we have the
pharmacologic therapies, medications; and we have the brain stimulation therapies
which began with electric convulsive therapy but now have expanded to include other
modalities that Dr. Lisanby, M.D. will tell you about. And then we’ll hear from Dr. Blair
Simpson who will speak to you about her work in Obsessive Compulsive Disorders
and then I will speak to you about an update in the current status of treatments for
Schizophrenia and then Dr. Pardes will provide concluding remarks to synthesize the
presentation and talk about the future.
For the people that are standing in the back, there are seats that are up here so
please come forward if you’d like to.
So without further ado, it’s my pleasure to begin the program by introducing Dr. Holly
Lisanby who is a Professor of Psychiatry at Columbia and Director of the Division of
Brain Stimulation and Neuromodulation. Dr. Lisanby?
Sarah Holly Lisanby – Columbia – Professor of Psychiatry
Thank you and good afternoon. It’s truly a wonderful privilege and honor to participate
in this very important event that is going to do, go to great lengths to help to shed light
on the importance of cutting edge research to address the problem of psychiatric
disorders and finding novel treatments. My talk is going to be about brain stimulation,
offering new hope when medications fail. And the origin of this talk really starts with
the problem of treatment resistance.
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While we have had wonderful progress in discovering causes and treatments for our
brain-based disorders, there is still a long way to go in finding an answer for every
person that is suffering from these disorders and helping their families. Regarding the
outcomes with unipolar major depression, major multi-center trials sponsored by the
National Institute of Health taught us that although almost half of people will respond
when given their first antidepressant medication- of course we have need to do
something about the other half as well. And the issue is that the chances of
responding to a medication after a person has failed to respond to their first
medication, is lower. Here you see the likelihood of responding goes down to 27%
after a person has already failed one medication trial, it goes down further to 15%
after that person has failed two trials and after they’ve failed 3 trials, it goes down to
12% and this problem of medication resistant depression is a very serious problem
that results in a great deal of suffering and disability for people and for their family.
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The situation is not much more rosy in people with bipolar disorder who also have
major depression. Major NIH sponsored trials such as the Step DD study taught us
that unfortunately anti-depressant medications were less effective in this condition
than might have been previously thought and in fact one study failing to find a
difference between anti-depressant medications and a placebo or sugar pill. So what
this really means is that effective alternatives are sorely needed. So that’s where the
good news comes in. Brain stimulation really does offer hope in finding solutions for
people when medications are not fully effective.
Probably you’re familiar with the gold standard brain stimulation technique that we
have in psychiatry and that’s called electroconvulsive therapy or ECT and the good
news about ECT is that it’s the most effective and rapidly acting treatment that we
have for depression. It also has a very broad therapeutic spectrum showing benefits
not just in depression but also in bipolar disorder, people with mania that are not
responding to medication, people who have psychosis whether it’s affective disorder
or schizophrenia that fails to respond to medication, people with catatonia who are
among the more severely and acutely ill, ECT is profoundly effective in persons with
these serious conditions. And recent research has modernized ECT to improve its
safety profile so that outcomes can be excellent with fewer side effects.
But that being said there are some limitations with the way that ECT is conventionally
administered. First of all there’s a significant concern about cognizant side-effects, in
particular loss of memory or amnesia. Recent studies sponsored by NIH have
suggested that some of this memory loss may linger longer than previously thought,
with some forms of ECT. Here you see a study by [INAUDIBLE13:45] colleague
showing autobiographical memories for us. This is memory for events in your own
life, it’s something that certainly people who are facing ECT care a lot about, you want
to remember your past and the bars going below the zero line, show persisting loss of
memory about people’s lives lasting up to six months after receiving a course of some
forms of ECT.
A second issue regarding ECT is of course its therapeutic benefit is excellent but we
want that benefit to last long-term so that people can remain well long-term and not
have relapses in their condition. Unfortunately recent studies have revealed that in
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some cases the therapeutic benefit of ECT fades with time. This study by Charlie
Kellner and colleagues shows the percent of people remaining well after they’ve
responded to an effective course of ECT over a six month period. You see the red
curve and the yellow curve going down as a function of time over that six month
period, that represents about 50% of people losing the benefit from ECT in the first six
month regardless of whether they were continuing to take medication on the yellow
line or continuing to take ECT in the red line. So of course these limitations of
conditional ECT are a significant concern, so clearly new hope is needed and that’s
where this talk begins.
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The good news is that of course we still have ECT and we use it with modern forms of
it that improve the side effect profile but today brain stimulation in psychiatry is not just
ECT but rather we have a growing number of new technologies, mostly with three
letter acronyms which we’ll be going through that offer new ways of stimulating the
brain to offer hope when medications fail. Together these technologies represent a
brain stimulation family and as Dr. Lieberman introduced – a new paradigm for
treatment in our field today. Some of these technologies use magnetic fields to
stimulate the brain, they include transcranial magnetic stimulation or TMS, we’ll be
talking more in depth about that which recently became FDA approved for the
treatment of depression. There is also magnetic seizure therapy or MST which is
investigational which seeks to use some of the noninvasive nature of magnetic fields
coupled with the powerful therapeutic efficacy of seizure therapy.
Some of these technologies require a surgical implantation, and they are called vagus
nerve stimulation of VNS where a pacemaker type device is implanted into the chest
and electrodes are tied onto the vagus nerve in the neck which is one of the cranial
nerves and by chronically stimulating this nerve, they can change brain function.
Then there’s also deep brain stimulation or DBS where again you have a pacemaker
implanted but this time the electrode goes directly into the brain, into deep areas of
the brain that are implicated in our disorders. And then finally there are the electrical
treatments in addition to ECT, there’s transcranial dry current stimulation or TDCS
which administers weak currents to the scalp to change brain function. What these
technologies have in common is that the brain is an electrical organ. That means that
it responds to electrical and magnetic stimulation. As with the heart in cardiology we
have both medications that affect heart function and also electrical therapies like
pacemakers and defibrillators. Likewise, because the brain is also an electrical organ,
in addition to pharmacological approaches we now have electrical and magnetic
means of changing brain function and modulating circuits.
The first one I’ll introduce you to is called transcranial magnetic simulation or TMS. In
the video, you’re watching actual subject receive TMS. We’re placing electrodes on
his hand so that we can record the twitch induced in his hand muscle when we
stimulate the area of his brain that controls movement in his hand with the TMS coil
being held on his head here. You see, we’re holding the coil over the area of the
brain, the motor cortex and the magnetic field is entering his head, passing through
the scalp and skull without impedance, so noninvasively, no anesthesia is required.
You are about to see a twitch in his hand and we’ll also show the tracing on the
electromyograph which is the electrical evidence of activation of his hand muscle.
What we’ve done by exposing his brain to a magnetic field, it’s that magnetic field has
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induced a small electrical current in a targeted focused region of the brain, in this
case, the motor cortex. That message is then passed down to the spinal cord and all
the way through the nerves that connect onto the hand to cause a twitch in the hand.
So what we’ve effectively done is activated a functional circuit in the brain and the
body. TMS is non-invasive because as you saw, it uses magnetic field, no anesthesia
is required and a seizure is not induced. We call it neuromodulation because we are
activating neurons and we’re activating circuits and by repeatedly doing so, we can
change the functioning in those circuits in a lasting way. TMS has become a very
useful tool in neuroscience, helping us to study relationships between brain areas and
functional outcome and behavior. It’s also now become an available treatment tool
when it recently received FDA approval for the treatment of some forms of
depression.
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And so brain stimulation offers new hope for persons with psychiatric disorders that
are not responding to medications for a couple of reasons. First of all brain
stimulation helps us move from correlation to causation. What I mean by that,
correlation means that with function neuro-imaging and neurophysiology tools, such
as an FMRI scan showed here, we are discovering linkages between brain circuits
and behavior and function. But brain imaging and neurophysiology are passive tools,
they basically listen and record to what is going on in the brain, but they can’t change
what’s going on in the brain. And to discover the underpinnings of our psychiatric
disorders, we need to do just that. That would enable us to do true hypothesis testing
so that we can go in and test what these areas of the brain do so that we can
establish causation. This is important because once we know the cause then we’re
going to be much closer to finding the cure. So we do that by applying focal brain
stimulation such as TMS to different nodes in these networks and changing function in
these regions and then asking what impact that has on outcome. So it’s helped us do
true hypothesis testing.
The second way that brain stimulation can offer new hope for people with psychiatric
disorders is it helps us move from knowledge that we have been acquiring about brain
function and psychiatric disorders to treatment that could be administered in a medical
office based setting, that would leverage the accumulated knowledge from neuroanatomy, neurochemistry, physiology, brain imaging that has revealed information
about the underlying disorder and then allow us to stereotactically deliver focal brain
stimulation to the circuits that are implicated to turn this into a useful treatment. Of
course it is important to do the studies to gain knowledge about brain function but at
the end of the day, what we really want is to turn that knowledge into an effective
treatment. Brain stimulation helps to do that.
And so as Dr. Lieberman mentioned in his introduction, brain stimulation really does
represent a paradigm shift in psychiatry today. Of course we have psychotherapies
that are highly effective for many conditions either alone or coupled with
pharmacotherapies. Now, in addition to those two domains, we have
neuromodulation therapies that stimulate brain function using electrical or magnetic
fields. Together, these three approaches offer unprecedented therapeutic options for
people who are suffering from brain-based disorders. They also offer new tools for
discovering the basis of these disorders on a biological basis. To give you an
example of that, here is a circuit diagram from work by Helen Mayberg and colleagues
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that illustrates some of the brain areas that are implicated in depression. And of
course, it is a complicated distributed network. The idea is by stimulating one node in
that network such as these deep prefrontal region called the rostral cingulus, when
that region is stimulated with deep brain stimulation, by actually putting the electrode
in that location and giving small electrical pulses. This can change functioning in the
rest of that network and in fact changes have been seen, not just at the site of
stimulation but also at these prefrontal regions that are also implicated in depression.
Dr. Mayberg’s work has shown when baseline functional imaging is done, in people
with depression, the targeted region shown in red here, that rostral cingulate region is
hyperactive whereas these lateral frontal regions are hypoactive, under functioning.
After three months of stimulation of the rostral cingulated, head imaging revealed that
the stimulated area was now cooled down so activation there was reduced and
activity in these lateral frontal regions was turned on again. And those changes in that
distributed functional network also underlie depression were associated with clinical
improvement in these people with very severe depression that had not responded to
any other treatments available today.
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Going the other way, using a non-invasive brain stimulation technology such as
transcranial magnetic stimulation, we can stimulate some of these lateral regions of
the cortex such as the lateral prefrontal cortex and see changes in deeper brain
structures such as these midline prefrontal regions. This is work by Mark George and
Colleagues and by the way, I should say that both Dr. Mayberg and Dr. George
received NARSAD funding for the work that I am showing. Dr. George’s work found
that after stimulation of this lateral prefrontal region, there were increases in activation
at the site of stimulation and also at these midline prefrontal structures. And changes
in that distributed network have gone hand in hand with clinical improvements in
depression as shown in this study. This study examines the anti-depressant values of
exciting there areas in the depression circuit. In this case, TMS was used to try to
normalize activation in the prefrontal cortex. This was a very rigorously controlled trial
of TMS given to the left prefrontal cortex in just over 300 people who were suffering
from severe major depression. And the blue bars, you see the percent of people who
were responding after 2, 4 and 6 weeks of treatment with TMS compared to grey bars,
the percentage of people responding to a sham or placebo intervention.
And so there was significant anti-depressant effect of stimulating this part of the
depression circuit. Not only is this important for helping people recover when
medications alone are not working. It also helps us understand how the circuit works.
If we are right, that this area of the brain is important in the circuitry of depression,
then normalizing activity there should be associated with clinical improvement and
indeed it was. And so now, TMS is FDA improved for certain forms of depression, not
all forms of depression. So it is important to seek advice from your healthcare
provider.
Moving on to other examples of circuit based treatment using focal brain stimulation.
Now we are moving into areas that are not yet FDA approved; that are investigational.
The first one, applies TMS to circuits that are thought to underlie schizophrenia and in
particular, auditory hallucinations. This is work by David [INAUDIBLE] and colleagues
showing that when people with schizophrenia hear voices, there is increased
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activation in a variety of regions of the brain and in particular, the left temporal parietal
junction. And so since that area of the brain was hyperactive, Rob Hoffman and
colleagues who is also a NARSAD funded investigator, sought to dampen down
activities at the area of the brain that was abnormally hyperactive. And he did this in a
controlled study of TMS given precisely to that region and here you see the results.
The blue line shows the reduction in the frequency of auditory hallucinations during
active TMS compared to a placebo controlled condition in red and very importantly,
half of this sample continued to show benefit at 15 weeks after finishing the TMS and
so there was some evidence of lasting effects. This result has been replicated by
other centers and Dr. Hoffman and colleagues are extending this work.
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Another example from one of our investigators here at Columbia, Dr. Antonio
Mantovani, collaborating with Dr. Blair Simpson who we will be hearing from next, has
studied the clinical effects of normalizing activity in circuits underlying obsessive
compulsive disorder. This work was informed by brain imaging studies,
neurophysiology studies of OCD, this one showing areas of the brain that are
hyperactive in keeping with OCD compared to healthy volunteers and one region that
we targeted was the supplementary motor area which is at the top of the brain.
Because this area was hyperactive, we used an inhibitory form of stimulation, a low
frequency TMS stimulation and this was a rigorously controlled trial of TMS given to
the supplementary motor area and we did this in persons who had obsessive
compulsive disorder that had failed to respond to multiple courses of medications and
psychotherapy. What we found was a significant reduction in OCD symptoms shown
in the blue line after two and four weeks of TMS to this area of the brain compared to
a sham condition in grey. In our sample, 67% of people receiving active TMS
responded compared to 22% receiving the placebo. But the study suggests not only
is that this might be a fruitful avenue for future research for it’s treatment in medication
refractory OCD but it also helps to inform us about what role that region of the brain
plays in OCD circuits.
Moving on now to magnetic seizure therapy or MST, which we have been studying as
a safer form of seizure therapy. Here you see in the video, a person receiving actual
MST, it is done in an ECT suite under anesthesia – carefully controlled anesthesia.
The treatment is being demonstrated here by my colleague and collaborated Dr.
Mustafa Hussein. In the case of MST, the goal is to take what is good about magnetic
fields, that is that you can focus them very carefully and they are non-invasive and
couple that with what is good about electrical ECT, or seizure therapy is that it is so
powerfully effective. Our goal is to reduce the cognitive side effects of ECT. By
focusing the seizures to areas of the brain that are important for recovery and by
sparing the regions of the brain that are implicated in side effects, in particular
amnesia. In our work to date, we have shown feasibility of inducing seizures focally
using magnetic fields. We have also done physiology studies showing that we are
indeed able to spare key regions of the brain such as the hippocampus from exposure
to the electrical field shown here, the amount of field induced in deep brain areas with
MST in the blue bar compared to ECT in the red bars. We have also found evidence
of sparing of cognitive function with less degree of amnesia with MST in the blue bars
compared to ECT in the red bars. And finally, in preliminary studies, we found
preliminary evidence of anti-depressants efficacies. This line graph shows reduction
in depression scores following a course of MST.
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And so, to sum all of this up, I would say that there is great reason to believe that
there is new hope being offered by brain stimulation and psychiatry today. This offers
hope to help us discover what would otherwise be unknowable about brain function,
working hand in glove with functional mirror imaging and physiology studies, brain
stimulation offers and unprecedented tool to tease apart the circuits underlying our
disorders so that we can get closer to causation which will help point us towards cure.
Brain stimulation also offers new hope in terms of treating the otherwise untreatable,
providing a broadened palate of tools for people and their health care providers to
choose from to help them achieve recovery and sustain remission long term because
of course, that is the most important so that ultimately no one would have to make do
with ineffective or intolerable treatments. But to realize that hope of better living
through electricity, it is going to take a lot of work. We need more research. What I
was showing you was just the tip of the iceberg about what has been done and we
need more research to really optimize these tools, to know how best to deliver them,
at what dosage and what brain regions and to discover what predicts response to
these treatments so that we can identify who is most likely to benefit from these
interventions.
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NARSAD has played a leading role in supporting much of this work. I am showing
you here the photographs of just those investigators in my own groups that are
currently receiving NARSAD funding to help stimulation their neuromodulation
research careers and the seed that NARSAD has planted has grown into a great
flowering tree leading to more support such as from institutional sources, from other
foundation sources and from NIH. I show you here those investigators that have
received awards or those that have awards currently in review. And so, we are
expanding the research teams so that we can discover how best to make use of these
tools to help people with brain-based disorders recover. I would like to acknowledge
first of all, the patients and families that have participated in the trials that I have
briefly reviewed for you today. I would like to also give my sincere thanks to NARSAD
for their support. I feel very fortunate to have been a recipient of three NARSAD
awards, The Young Investigator, Independent and Distinguished Investigator Awards.
That really came at critical times in my own research career and enabled me to learn
about this field and to make contributions. And the other funding agencies of course
National Institute of Health, other foundations as Stanley Medical Research Institute,
American Federation of Aging Research and the device manufacturers who have
contributed. I would like to recognize the members of our division of brain stimulation,
Columbia Psychiatry. It is a multidisciplinary team with engineers, experimental
psychologists, neuropsychologists, psychiatrists, social workers, nurses, it really takes
a team, multidisciplinary and interprofessional team – so thank you to everyone. I
have left time for questions today but if we don’t have time to answer your questions
today, please feel free to call us or email us and here are the numbers and email
addresses. We are happy to share any information about the work that is going on in
the field in general and at Columbia Psychiatry in particular. We do have access
studies underway with each of the tools that I introduced you to today across a range
of disorders and so I would like to thank you for your attention and thank you again for
the chance to address you today and I am happy to answer your questions.
<Q>: [INAUDIBLE].
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NARSAD Webinar
April 10, 2010
Sarah Holly Lisanby – Columbia – Professor of Psychiatry
I’ll just repeat so that everybody heard. The gentleman was asking a question about
whether TMS would be a viable treatment to think about in a person who had received
ECT before in particular over 100 treatments since 1980 and I think of course each
individual case differs but I would say in general the response rate to TMS is lower
than what we typically get with ECT but it’s safer and so in sorting out when would you
use ECT versus when you would use TMS, it depends on how severe the situation is
at the time. One of the things that we are interested in exploring is whether TMS or
other neuromodulation technologies could be useful in helping people sustain benefit
after they get well from ECT, which sounds like maybe the situation that you are
describing. You’re saying things are going okay but should TMS be something to
think about in the future. I think in cases of, if there is a mild return of symptoms that
might be something to consider but we do need more research to see whether TMS
could help people sustain remission after responding to other treatments so that is a
wonderful question. Thank you for asking that.
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Oh, and Dr. Lieberman was asking what about Magnetic Seizure Therapy, yes. That
actually is something that we are using on a research basis to test whether it could be
as effective but safer than ECT and so we are using that in people who have had ECT
before. Maybe they benefited from ECT before but they are looking for an alternative
that might have fewer kinds of side effects. So thank you for that Dr. Lieberman, that
would be probably even a more appropriate thing to consider in your circumstance.
<Q>: [INAUDIBLE]
Sarah Holly Lisanby – Columbia – Professor of Psychiatry
Yes, the question is whether this has ever been used in movement disorders and that
is a wonderful question. In fact, we do have a study underway right now using TMS in
the treatment of Tourettes disorder. So a condition with involuntary movements and
vocalizations, we have published a study, this is work by Antonio Mantovani. Our
published study showed improvement when stimulating an area of the brain that is
related to the control of motor planning and we are following up that result now with a
controlled trial and this is collaboration with Dr. Joe Lechman and colleagues at Yale
to look at whether this can be a useful treatment. TMS has also been studied in other
movement disorders such as Parkinson’s disease and we have done a study on that.
Actually ECT is also helpful at certain circumstances of Parkinson’s disease so I think
that, but we do need more work to see what role TMS might have in those conditions.
<Q>: [INAUDIBLE]
Sarah Holly Lisanby – Columbia – Professor of Psychiatry
So the question is how long does the improve ….
<Q>: [INAUDIBLE]
Sarah Holly Lisanby – Columbia – Professor of Psychiatry
So thank you for your question and just to be sure I didn’t mis-state, it dampens down
meaning it sort of quenches an area of hyperactivity that is hyperactive in people who
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N.A.R.S.A.D.
NARSAD Webinar
April 10, 2010
are hearing voices and work by Dr. Hoffman and colleagues sustained improvement
over a 15-week period which was as long as they showed in the study. I do believe
that he has other studies underway looking at whether the effects could be longer
term. Of course we need a longer term solution in that situation because it is a long
term situation and people do need long term treatment. You know, one of the things
that most of the studies initially look at acute response and then the next area where
research is really needed is to look at long term followup so that we can understand
how best to use medications, psychotherapies and brain stimulation to help sustain
remission in all of these disorders but that is a wonderful question. Thank you.
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<Q>: [INAUDIBLE]
Sarah Holly Lisanby – Columbia – Professor of Psychiatry
So the question is whether these studies have looked at dual diagnoses of chemical
addiction. So there’s actually, that is an area of opportunity. It is a serious situation.
Of course we know that psychiatric disorders, schizophrenia and other disorders have
a high degree of comorbidity with substance abuse and dependence and it can
become a vicious cycle where one has to address both conditions to really help the
person in a meaningful way. Most of these studies excluded people who were having
substance abuse or dependence situations. There are a few studies that have looked
at brain stimulation specifically for substance use disorders. One has looked at
nicotine dependence and there is some exciting work looking at areas of the brain that
could be stimulated to reduce nicotine dependence. A few have looked at the circuits
underlying other substances of abuse such as cocaine. Actually I collaborated on one
of these studies along with Nash Butrose and colleagues at Yale. Using these brain
stimulation tools to study the underlying abnormalities, brain basis in people who had
abused cocaine. But in terms of treatment for substance or dual diagnoses, I would
say that is one of the most important future areas for research.
<Q>: [INAUDIBLE] addiction but there is relatively little going on in terms
[INAUDIBLE] solely an area which can be [INAUDIBLE]
Sarah Holly Lisanby – Columbia – Professor of Psychiatry
Yes so the question is can I explain how brain stimulation is helpful in these conditions
and that is a very important and complex question. I will just briefly explain
mechanisms. So both the magnetic and electrical stimulation therapies induce an
electrical current in the brain. So the active ingredient is electricity. Well what does
that electricity do I think is what your question is. What that electricity does is it
actually activates the neurons or brain cells causing them to fire so by inducing a
small electrical current in the primary motor cortex, it is activating those motor cortical
cells and that electrical message is passed down through the rest of the circuits
causing a twitch in the hand. So that is a simple case. I think your question is well
how would that help in depression? Or how would that help in schizophrenia. So by
repeatedly activating these circuits, you can actually change the long term functioning
in these circuits. The mechanisms underlying this are probably physiological and
neurochemical and some of this has been studied by repeatedly using a circuit, you
can enhance the facility of future use of that circuit. This is a mechanism of
neuroplasticity that’s also called Long Term Potentiation or LTP which is thought to
underlie some of our basic normal brain function like memory. And so it is
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hypothesized that these brain stimulation techniques act by inducing lasting changes
in neuroplasticity in different brain circuits and I could go on and on about
mechanisms but I am also happy to answer questions in more detail. It is an area that
we are studying, certainly another group are publishing papers on that mechanism.
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<Q>: [INAUDIBLE]
Sarah Holly Lisanby – Columbia – Professor of Psychiatry
And so Dr. Lieberman is asking could I look at re-booting. Well that is a way that
some people have described a mechanism of action metaphorically, sort of resetting
the state of a circuit and it is a metaphor that many people who have received brain
stimulation use themselves in describing the experience but I think that what we are
trying to do is modulate and normalize activity in a connected network by dampening
down areas that are hyperactive, elevating up areas that are underactive,
reconnecting areas that aren’t talking to each other as well as they should be to try to
normalize functioning in that circuit,
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Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
I think it is important to point that ECT has a checkered history [INAUDIBLE] so
notoriously it’s very highly effective [INAUDIBLE] places using the most sophisticated
techniques [INAUDIBLE] to be sure but for the conditions in which it is indicated, there
is nothing better and it is highly safe and nobody has to go through or [INAUDIBLE]
side effects as a result.
Sarah Holly Lisanby – Columbia – Professor of Psychiatry
Yeah, so I would like to agree with Dr. Lieberman’s point that great strides have been
made in improving the outcomes of ECT, making it safer than ever before. I would
just add to that that there is considerable variation in practice in how people
administer ECT and so it is very important to speak with your health care providers
about what type of ECT that you are receiving because it is not one size fits all and
there are different aspects of the ECT dosage that are critically important in
preserving memory and improving outcomes.
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
[INAUDIBLE] with the idea of getting ECT. You know, it’ll destroy his brain, his
memory will be impaired [INAUDIBLE].
Sarah Holly Lisanby – Columbia – Professor of Psychiatry
So thank you for the comments and I share your admiration for NARSAD and thank
you for following our work. I think it is important when we are doing developing new
interventions, that we test them for safety before we use them in our patients and
families as we do test all of our medical treatments across all of the disciplines of
medicine today.
<Q>: Mr. Callaghan had a question about the use of [INAUDIBLE] in research.
[INAUDIBLE] on your strict code of regulations [INAUDIBLE] we wouldn’t be able to
maintain any forward movement in terms of advanced [INAUDIBLE]
Sarah Holly Lisanby – Columbia – Professor of Psychiatry
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N.A.R.S.A.D.
NARSAD Webinar
April 10, 2010
Right so the question just so everyone could hear is what about a situation of very
severe and debilitating, a combination of schizophrenia and OCD and it also relates to
the previous combination of dual diagnosis and this, you’re highlighting that some of
these people have multiple brain-based psychiatric disorders as well and that is a very
difficult situation. It would be difficult to comment on the particular case of your son
without looking at the records to know the treatment history but I would say that’s an
overlap that we do see not uncommonly and with combination of medications and
sometimes brain stimulation technologies, improvements can be seen. I would be
happy, if you would like to followup with me after the presentation to give more details
but I would also just make the general point that when we show these studies about
something offering hope in specific context, the trials don’t always test the techniques
on the real world situation where a person had their unique experience of the illness
and they may have multiple illnesses to contend with and that is the challenge that we
also, not just as researchers but clinicians face every day so I would be happy to
followup with you afterwards.
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Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
[INAUDIBLE]. Thank you very much Holly. For anybody that wants to review this
again, this whole program will be posted on the NARSAD website subsequently.
Also, let me just mention that there will be a conference that is held here at Columbia
on April 25th which is the 25th Annual Schizophrenia Conference for members of the
general public. It started 25 years by Dr. Martin Willic and some of his colleagues
and Dr. Willic is here with us today also. So for information about that meeting you
can go to the Columbia Psychiatry website and it will be listed.
So it is a pleasure to introduce our next speak who is Dr. Blair Simpson who is an
Associate Professor of Psychiatry and Director of the Anxiety Disorders Program at
Columbia. Dr. Simpson?
Blair Simpson, M.D. – Columbia – Associate Professor of Psychiatry
Thank you. Okay, let me get set up. Well thank you Jeff for that introduction. I run
the Anxiety Disorder Clinic here at Columbia and the New York State Psychiatric
Institute and there is a spectrum of psychiatric disorders that are characterized by fear
and anxiety which we call the anxiety disorders and there are many different types. I
am going to talk to you today about obsessive compulsive disorder or OCD. It is not
the most common of the anxiety disorders but it is the most severe and in my talk I am
going to focus on what is it, make sure that we are all on the same page, how do we
treat it? What do we know about what causes it? And finally, how can research help?
Now I know that there is a lot of talk about, it is very important I think for an audience
to know who is talking to you, who am I and where do I come from and one way I can
tell you about that is to acknowledge my funding and the important point of this slide I
think is that the majority of my funding comes from the National Institutes of Mental
Health and some foundations and I am very grateful to NARSAD who also gave me a
Young Investigator Award at a very key moment in my career and I don’t think I would
be here today if it hadn’t been for that key moment of funding. And I have very little, I
have some interaction with industry but very little and for most of my career, I have
really been focused on both psychotherapy and psychopharm research.
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NARSAD Webinar
April 10, 2010
Now, let me start by what is OCD? And I am sort of curious by a show of hands if you
would humor me, which is, in the audience, how many people know someone or think
they know someone with OCD? Okay. So that’s great you know because a lot of
times I speak to audiences who don’t know much about it. So that’s great. Let’s see
if we agree. So the hallmarks of OCD from our perspective, if someone has
obsession and compulsion. And what do we mean by obsession? By obsession
through means of repetitive thought, impulses or images that are intrusive,
inappropriate or unwanted might be a better word which is what I hope the
[INAUDIBLE] is going to shift too and very distressing. What do we mean by
compulsion? Repetitive behaviors or mental acts that the person driven, feels driven
to perform to reduce the stress or to prevent a feared outcome. Now all of us, you
take anybody without OCD, all of us have funny little thoughts from time to time. You
know, have you ever stood at the top of a high building and had that funny little
moment of sort of a weird little impulse to jump? Or maybe even had an image of
yourself down at the bottom? Have you ever let’s say gone on an air plane trip and
checked more than once whether you had your airplane ticket in your bag? That is an
OCD. Those are funny little thoughts that float into our minds. You might notice it,
you might not notice it and it just goes in and it goes away. And some of us have a
little bit more habit. You know, your colleague who has a few little habits about what
he does with his waste paper basket for example at the end of the day. Again, that is
an OCD.
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To be OCD, you have to have symptoms, obsessions and compulsions that are
distressing, generate anxiety or distress, are time consuming and a usual sort of
yardstick we use is at least an hour a day. But my patients are usually obsessing and
compulsing six, eight, ten hours a day and the important point is that these symptoms
are impairing the functioning and the quality of their life. So there are other clinical
features about OCD that are important and one of them is that while all patients with
OCD have obsessions and compulsions the actual specific obsession or compulsion
can vary a lot and what I am sure you hear are just a range of different themes that
different types of obsessions can have and I am listing for you a range of different
types of compulsions we see. So usually what people know about are the OCD
patient who has intrusive fears about germs or dirt or contamination of some sort and
who then is doing a lot of washing or cleaning. But for example, another very
common form of OCD is intrusive thought that harm might befall themselves or
someone else and that could lead to a lot of checking compulsion. Then there is the
person where everyone has to be, everything has to be just so or perfect and these
people might be consumed with ordering and arranging things all day long. Etc., etc.,
etc. So there are many different manifestations about OCD and it has led people to
think, well gee, are people with all these different types of symptoms, is it all really the
same illness, or by chance, are there different patterns of genetic transmission or
neurobiology or treatment response that sorts along these different symptom types.
And what I would say is it is still a very unanswered question in the field, but the one
area there seems to be the most data on are the people who have compulsive
hoarding or collecting of items and I don’t know if anyone here has been watching
those, there has been a lot of television press on the problem of compulsive hoarding
and that has historically been under OCD. But now there is a thinking of people who
only have that symptom type, it might really be a distinct disorder because in fact, the
treatments that we have for OCD don’t usually work as well and it is an area, I won’t
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April 10, 2010
talk more about that in my talk but it is an area that here at Columbia we are
extremely interested in and I have research fellow who has been doing some very
interesting work with people who are being evicted from their homes and looking at,
you know, how much does hoarding play a role in eviction or homelessness in New
York city and we are particularly interested in what could we do to develop novel
treatments for people with compulsive hoarding?
There are other clinical features of OCD that are important to know about. One is and
I emphasize this when I described what a compulsion is, and compulsion and ritual, I
have used both those words, they are really one and the same thing. The point is,
they can be behaviors that you see, like repetitive washing but they can also be
thoughts. So for example, someone can have the intrusive image that they are going
to stab their mother and they are horrified by this thought. That is an obsession. But
then, to try to neutralize that thought or that image, they might call up a positive image
in their minds, let’s say of their hugging their mother or some alternative image. That
is the compulsion or the ritual. The thing that they are doing over and over and over
again to try to reduce the stress. We call that a mental ritual. And so the point being
is that not all OCD can you see. It can actually be something that a person with OCD
can be doing all in their heads.
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Another point is that in fact the content and the fear can be relatively bizarre and I
could tell you a lot of different stories and you would think gosh, that’s a little odd.
Historically, those people were often diagnosed as psychotic and they might have
ended up with a diagnosis of psychosis but we actually now know that they’re, and
again, it varies depending on the study but maybe 5 to 10% of people with OCD really
can very bizarre thoughts. This isn’t the most bizarre but let me give you an example.
I worked with a doctor who had the thought that if the word leukemia popped into his
head at the dinner table, that he might actually give his child leukemia. Now he was a
doctor. He knows that that isn’t how you get leukemia. But that was his OCD. The
other thing is that the insights about the symptoms can also really vary and I mean
vary within a person and I mean across people and so I have patients who show up in
my office who say I am washing my hands three to six hours a day and I know it’s
nuts but I can’t stop. I know I don’t need to do it but I can’t stop and I have other
people who are really not sure, or really feel they have to wash their hands or they
might kill someone. So there is a big range in how much insight there is and as you
can imagine, people who don’t have insight into the illness, it makes treatment that
much more difficult.
Another important point is that there is a lot of comorbidity in OCD. By comorbidity I
mean other disorders that come along that the person has at the same time. The
most common are depression, all sorts of different forms of depression and all sorts of
other anxiety disorders. But there is also this triad of early onset males who get OCD,
tic disorder with Tourettes and Attention Deficit Disorder that sort of comes in a triad
unfortunately. Then there are these things that we call OCD spectrum disorders
which if you will are sort of lookalike OCD disorders like skin picking. Sometimes
pathological gambling is put here. There are aspects of anorexia that are OCD-like.
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April 10, 2010
And finally, the other major medical illnesses like schizophrenia, autism and bipolar
disorder, we now know that those patients have a much higher rate of OCD than they
should have by the prevalence in the population.
The other major medical illnesses, like schizophrenia, autism and bipolar disorder.
We now know that those patients have a much higher rate of OCD than they should
have by the prevalence in the population. And there’s some studies with
schizophrenia that may be up to 20% of patients with schizophrenia have, meet all
criteria for OCD comorbidly and it makes treatment a challenge.
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My final point and sometimes it’s surprising to people, is to emphasize how disabling
the disorder is. So I’d like to point out, it’s more prevalent than schizophrenia.
Schizophrenia lifetime prevalence is 1%. I’d like to point out that the median age of
onset, meaning half the cases by age, what time they start is 19. The age for major
depression is 32. And quite tragically, at least a quarter of the cases start by age 14.
So I’ve had patients who remember in retrospect, they show up for treatment in their
30’s, but when they think back, they realize that at the age of 6, they were lining up
their teddy bears in a row over and over and over again. The other thing is that the
illness is not always but often chronic with a waxing and waning force. If you put all
this together, 2% prevalence, early onset, typically chronic course you can see, oh
and I’m sorry in the last part, which is when you have this, it has a high tendency to be
serious or moderate to serious in symptoms, not on the mild end. When you put that
all together and you can see that this is an illness that can really get people off track,
early in their life and really do a lot of damage to their functioning as an adult.
So let’s talk about treatments. The good news, well there’s good news and bad news
unfortunately, right. The good news is we do have two treatments that work for OCD.
And I’m going to tell you a little bit about each in turn. One is a class of medications
called serotonin reuptake inhibitors are often called SRIs and the other one is a very
specific type of therapy, cognitive behavioral therapy which has been called or sorts of
things in the literature. You’re going to hear me call it exposure therapy or exposure
and response; you’re going to see it on the slides as EXRP.
Let’s start with medications. There’s a class of medications called serotonin reuptake
inhibitors and I’ve listed them all here. They include clomipramine which is a tricyclic
antidepressant, an old-fashioned if you will antidepressant but has very powerful
serotonin reuptake inhibition as well as all of the selective serotonin reuptake
inhibitors. These are probably names that you’re familiar with, Prozac, Paxil, all of
these medications work on OCD, all of them and all of them are FDA approved for the
treatment of OCD except for Celexa and Lexapro and I think that’s just the drug
companies didn’t think they would make money so they didn’t go forward with getting
FDA approval because it’s a very expensive process, but they all work. The thing is
you need very high doses, we don’t know why, in general and you need a very long
time on that high dose to see a response. Again we don’t really know why. And there
are important limitations even when they do work. First of all, not everybody will
respond to them and a typical response is usually a reduction in symptoms, not
remission or like cure.
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April 10, 2010
So what do we do to try and improve our outcome from this class of medications?
Sometimes doctors will try to switch to another one or raise and raise and raise the
dose, in isolated cases that can be helpful but it’s not a very powerful approach. The
most evidence-based is for adding something on top of the serotonin reuptake
inhibitor. And the two things that we know work, is adding cognitive behavioral
therapy, and I’m going to tell you more about that in a minute, or adding very low
doses of the class of medications that have been called antipsychotics or dopamine
blockers. And I’ve listed some of the ones here. You probably are familiar with some
of these names. This is actually a very highly effective strategy in maybe up to a half
of people, but it’s one of those strategies where you want to try it. If it works, great
and if it doesn’t work you want to come off of it because these medications long-term
can have side effects. We’re currently at Columbia doing a study, comparing these
two strategies directly. So if there’s anyone in the audience or you know anyone who
hasn’t had these augmentation strategies and would like to get them at no cost to
them, you should give us a call, and I have flyers out front about our program.
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But then there’s a lot excitement about trying to develop novel treatments. You heard
from Holly about the work in transcranial magnetic stimulation, highly experimental,
there’s also, always there’s new things being tried in OCD. There’s a lot of excitement
in the field right now about novel medications that are thought to modulate the
glutamate system and I’m very grateful to NARSAD who gave a young investigator
award to one of my research fellows to explore one of those medications in OCD. I
think, it’s too early to tell but the data suggests that this class of glutamate modulators
might be very effective but only in a small subset of people with OCD. And it’s usually
as an add-it-on to the serotonin reuptake inhibitor. But again you’re right at the edge
of where research is at this point.
Let’s go back to the other treatment we know works for OCD. This is not experimental
and that’s exposure and response prevention. It’s a specific type of cognitive
behavioral therapy. So what do you do in exposure and response prevention? You
sit down with your patient and make a hierarchy of the things that they fear, the things
that trigger there obsession and you also make a long list, you really know what are
their rituals or compulsions and you ask them to stop doing all of the compulsions and
their rituals as fast as they can and together with you, you then work up that hierarchy
of things they’re afraid of with you and what you do are very prolonged exposures to
those situations. So it isn’t touch the toilet and remove your hand because that’s not
going to do anything at all. It’s putting here, for example, the person has a fear of
contamination and toilet seats are a big thing, it’s keeping your hand down there on
that toilet seat and letting time alone drop the anxiety. It’s been called in the literature
habituation, now we wonder is it really extinction, we’re not sure what’s the right
language to call it but what we know is that if you engage anxiety and you stay in the
anxious moment and can tolerate it and don’t do anything to try to escape it, in fact
just with time alone, the anxiety will come down.
So this is a very powerful treatment, I’ll show you in a second, it’s usually done in
individual sessions, usually the sessions are long because as you can imagine, you
want as a therapist to really work through the issues with your patient in the session.
You often go out to the field and do home visits because the goal is not that they can
touch the floor at your office or the bathroom toilet in your bathroom toilet, the goal is
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for them to be out in their real world environment and really to have address their
fears. And the point of the treatment or how we think about it is we’re trying to break
two associations that the brain has made. One, certain stimuli have to trigger anxiety
and the other one is that the only way to get relief is by doing the ritual. And in the
process, what we think we’re doing is shifting their mistaken or irrational beliefs. So if
you think that touching that subway pole is absolutely going to kill you and you go and
you touch that subway pole and you don’t die, that’s actually a very powerful, if you
will disconfirmation of the irrational belief and it’s much more effective to do it that way
then to say to someone, that subway pole isn’t going to kill you. It’s much better to
actually use the brain to break the association and that’s really what exposure therapy
is about.
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Now how effective is it and this is a study we did with Edna Foe at the University of
Pennsylvania directly comparing a sugar pill which is that line, clomipramine arguably
our most effective medication still to date or exposure therapy with or without
medication, delivered intensively over four weeks. And this is patients coming in at
week 0, high is bad, this is an OCD severity scale which goes from 0 to 40 and 16 and
above is usually what we would consider warranting treatment and needing treatment
and so our out patients will often come in moderately severe, somewhere in their 20s.
And what you can see I hope is that if you got a sugar-pill, not much happens over 12
weeks, if you get clomipramine you get a nice steady decline over 12 weeks and it
looks exactly like the trial that got clomipramine FDA approval, but look at the power
of exposure therapy delivered intensively by skilled therapists. You get a dramatic
decrease of symptoms in four weeks.
What happens, those were data from patients who weren’t on medication. What
happens if you start with, because most patients get medication as a first live
treatment, because it’s hard to find this treatment, it’s hard to find skilled therapists.
It’s also a scary treatment to do. What happens if you start on medication? These
are now a more treatment resistant population. Well here the therapy was developed
twice weekly and again over 8 weeks and again you see a nice decrease in their
symptoms, whereas if they got a control treatment, controlling for therapists time and
support, not much happened.
So what I’m showing you, I hope, is that this very specific cognitive behavioral therapy
called exposure and ritual prevention can be highly effective on its own, it can be
highly effective added to medication treatment if you’ve had a partial response to
medication, which is most people, but I also don’t want to leave you thinking, oh that’s
that cat’s meow because it unfortunately also has limitations. Oops, I’m sorry. As I
said, it can be hard for people to access it and it doesn’t work if you don’t have a
skilled therapist. It can be very hard for people to do it, the patient adherence is a key
issue and I think there’s an outstanding question about the long-term effects, because
it’s really a treatment where you’re taught a new skill and now that you keep using it.
And like for example if you think about a weight loss program, if you are in your weight
loss program and you lose those 20 pounds but you finish the weight loss program
and you go back to eating the way you did before, you all know what’s going to
happen. And if you will, cognitive behavioral therapy is the same thing.
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NARSAD Webinar
April 10, 2010
What are we doing to try to improve outcome from exposure therapy. One, and I’m
very grateful to NARSAD, they funded me to explore the use of motivational
interviewing to see whether we could improve patients adherence to exposure therapy
because we know that’s the key factor that really differentiates people from a really
good outcome versus not such a good outcome. And motivational interviewing is a
technique that’s been used in the substance abuse deal and was originally designed
for use for people with alcohol problems because there again the issue is how do you
motivate people to say no to the drink. And that’s a study that we’re just finishing up
now. The other way that other people are working on trying to improve outcome from
exposure therapy is actually to improve how much learning happens in each session.
And this, I have a colleague who has been funded by NARSAD to explore this in
children and adolescents. And the idea here is these D-cycloserine is a medication
that was long ago approved for the treatment of tuberculosis and it was used in rodent
models of fear conditioning, where they taught rodents to be afraid and then they
extinguished the fear and they found that if they gave the rodents D-cycloserine, they
extinguished much faster. So then the idea was well what would happen if you gave
D-cycloserine to a human while you did exposure therapy. Could you get the fear to
extinguish much faster and could you get better learning? These are examples, I’m
not giving you the answers because I don’t have them yet but these are examples of
the sort of innovative creative projects that NARSAD has funded and allowed those of
us in the field to explore new, little bit kooky but I think creative ideas that could
potentially lead to big impact.
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Let’s turn now to about the brain and what do we know about the brain and what
causes OCD. And I’d like to just sort of emphasize, the way I think about it is I think of
it as two different ways. One is what I call pathophysiology. And what I mean by that
is look, the fact that I’m talking to you today and moving my arms, that’s my brain
allowing me to do that and if I had a session in compulsions, than my assumption is,
something’s not right in my brain, but that’s a different question than etiology. The
different question that what caused my brain to be abnormal in the first place. I hope
you’re following me and see that difference. And so pathophysiology is just saying
what in the brain causes obsessions and compulsions. Etiology is what caused the
brain to be like that. The literature suggests there are quite a variety of potential
causes for brain abnormalities and OCD and we end up with OCDs and we don’t
know the full answer to this at all, this is a hot area of research. But we end up like we
end up with many of our psychiatric illnesses, maybe some bad genes, maybe some
bad environment and some either good or bad development along the way and really
sorting out that question, I think is a big challenge for all of us in the field.
Let me tell you about pathophysiology though because it’s hard to go after etiology
unless you know what the pathophysiology is. And here what we’ve learned from
brain imaging studies is that people with OCD, compared to people without have
abnormal activity in a particular circuit in the brain. And that circuit includes parts of
the frontal cortex, in particular the orbital frontal cortex which is involved in planning
and organization. It involves the basal ganglia and the basal ganglia has lots of
different components to it, including the striatum which is involved in making motor
plans and habits and it involves the thalamus is, one of its main roles is to filter
incoming information so that not everything hits our cortex and consciousness. It
keeps things out to let us be able to focus and function. The one theory about OCD is
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that the thalamus is not gating incoming information so all sorts of intrusive thoughts
are popping into these people’s brains and that is then overdriving the basal ganglia to
these compulsive behaviors. But obviously that’s a very simplistic narrative of what’s
going on and it’s obviously not the full story, but it’s a starting place.
The other thing that people have gotten interested in is okay well if there is abnormal
activity in this brain circuit what’s causing it. And usually what people think about
there is neurochemically, what’s not going right and for most of the history of OCD
there’s been a real focus on the brain chemical called serotonin, primarily because it’s
the only medications that affect the serotonin system are known to work in OCD. But
there’s been interest and there’s increasing interest in the dopamine and glutamate
systems, other major brain chemical systems. And what’s very exciting is that there’s
now evolving technologies for really being able to image the chemical systems in the
living human brain. And that’s particularly critical for an illness like OCD where there
are no studies of people who have died and donated their brain and their brain has
been studied and there’s no as yet validated animal models and the phenotype, the
clinical picture is so complicated that to be able to actually study the living human
brain of someone with OCD is one of our only handles for this condition.
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So to just describe to you a little bit how we do a study like this, I’m showing a
schematic of a serotonin synapse. The brain cells talk to each other through
electricity, as Holly was talking about but they also talk to each other through
chemicals. And I’m showing you the end of one brain cell, here, I call this the
presynaptic terminal of a serotonin neuron and it’s got little vesicles of pockets with
serotonin that it’s ready to release into this space which is called the synapse. And
the brain cells on the other side or the post-synaptic neurons have all sorts of
receptors here that when it hits one of these serotonin signals, it then changes its
functioning. Now this is a very simple slide, there are all sorts of presynaptic
receptors and many different types of post-synaptic receptors but bear with me, this is
really just to try to illustrate how we think about the nerve chemical system and how
we study it. One of the features of the serotonin synapse is that it has also got
something called the serotonin transporter. And how I like to think about that is that
it’s like a little vacuum cleaner and it comes out from the presynaptic cell, vacuums up
any remaining serotonin that is left in the space and picks it back up into the
presynaptic cell. If you will, it ends the conversation. So when you do a
neurochemical imaging study, one methodology you can use is positron emission
tomography or PET and you can actually go and ask about specific proteins in this
synapse and whether there are differences in your patient population or the healthy
control. And this is something that we’ve been doing in collaboration with Dr. Anissa
Abi-Dargham who is here at Columbia University who is an expert in this type of
imaging. And what I’m showing you here and it doesn’t show up very well because
it’s so dark, there are different slices through healthy control of brain, these are
different slices through people with OCD and the brain slices down here are just an
anatomical atlas to show you where you are. And the bright orange is showing you
where serotonin transporters are in the brain. And what I can tell you from the study
is we found no difference in the distribution of serotonin transporters between OCD
patients and healthy control. Now we’re finishing up a study where we’re starting to
look at the post synaptic receptors. It’s an example of how you can go and try to
study the nerve chemical abnormalities in your disorder of interest in the living brain.
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Another methodology that has been developed that can also do this, that has great
advantages is magnetic resonant spectroscopy and it’s got great advantages because
it’s not invasive and there’s no radiation and it’s a technology that you can thus use in
children and adolescents. It’s been developed to be able to look at glutamates which
is the major excitatory nerve transmitter in the brain as well as gaba, the major
inhibitory transmitter in the brain and we’ve been doing, in our PET studies we’ve
been imaging those same patients so we can look at the serotonin system as well as
the glutamate and the gaba system to see whether there are correlations between
abnormalities. And I actually have a proposal in front of NARSAD right now to try to
advance this methodology so that we have a much better way of looking at glutamate
per se in the brain areas of interest in OCD. But like with any scientific method and
we’re all going to tell you about all these oh cool wow, gee, scientific methods, like
everything in life, there are pluses and there are minuses and even neurochemical
imaging, while it’s opened up a whole view of the brain that we didn’t have 20 years
ago, it doesn’t answer all the questions and so for example, let’s say I could find
glutamate abnormalities in the orbital frontal cortex in my OCD patients as has been
hypothesized, I would know is that cause or is that the effect of the illness? I also
wouldn’t know which cell type because as you can see from those pictures, it’s sort of
a blob and a brain but in those brain areas are multiple different types of cell types. I
wouldn’t even know if it was a brain cell or some of the supporting cells necessarily. It
also, neurochemical data like that provides data on the availability of the chemical, it
doesn’t necessarily tell you anything about the functioning.
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And then there is a final issue, which is recruiting people with OCD and comparing
them to healthy control there is an assumption that everyone with OCD has the same
abnormality in their brain and the very well might not. So that’s lead many people,
including myself to think about, well how do you get at that more refined molecular
cellular look at what’s really going on in these brain circuits of interest in OCD and
that’s led people to be interested in developing animal models which has actually not
been very far advanced in OCD. My husband likes this slide, is the itsy bitsy spider
obsessive compulsive, no I’m not talking about giving OCD to an animal. Instead the
rationale for animal models is this. New pharmacological treatments are needed as I
hope you will agree with me. OCD has been associated with abnormalities in specific
brain circuits and now increasingly certain genes have also been associated with
OCD. So the question is could you use an animal model in a very targeted and
careful way and I appreciate the sensitivity about this, to study molecular and cellular
functioning. And could you use that to try to develop novel treatments.
And I just wanted to highlight one example of a study that generated a lot of
excitement in the field of OCD and you have to remember OCD has been one of
those disorders which really felt stuck for a long time. Serotonin reuptake inhibitors
are the only medication and we knew about in the 1970s, you know, so it really has
felt that we have been stuck in some ways in this illness. So this [INAUDIBLE1:23:12]
generated a lot of excitement and this was a group of researchers who the last thing
on their mind, I don’t think they knew what OCD was. They didn’t, I know they didn’t
know what OCD was, they were interested in some protein called Sef-hep[ph] 3 which
was a synaptic protein, you know in a synapse and [INAUDIBLE] in mice, you can
knock in and knock out genes, it seems almost like willy-nilly so they could take out
the gene from the striatum and low and behold, what happened in these mice, they
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NARSAD Webinar
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started to pathologically groom themselves to the point where they had bald spots on
their skin. When they put the gene back, just the striatum, they didn’t do it. They then
could take that math and really dissect exactly what it was about that gene that
actually caused problematic functioning and what they learned was it was in the
frontal striatal synapses, abnormalities and glutamate signaling.
Now with subsequent studies, the model may really be more suited towards what say
pathological grooming behaviors in humans, like skin picking and nail biting but I think
the study points out a couple of things. One is that you can actually remove one
single little protein in one single little part of the brain and actually get a complex
behavior, two it shows the elegance with which you can take a system like this in a
mouse and they could go in and exactly find out the specific proteins and signaling
abnormalities in a way that I don’t know that we’ll every really be able to do in
humans. I think it also points out the importance of linking the animal studies to the
human studies to make sure that what we’re pursuing in animals really is of relevance
to the human disorder that we care about.
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And in summary, you know what I hope I’ve, what I’ve tried to tell you about is that
OCD is a severe and disabling illness. We, you know really a lot about is the etiology
and the pathophysiology remains a mystery. We have effective treatments but both of
them, all of them have significant limitations and I think it really outlines to me at least,
my interest in continuing to do research in this area. And I see it as two ways of
thinking about it. We need research for the patients of today and to me what we need
is how to promote early identification and treatments. It’s heartbreaking to me to see
adult patients in their 40s who have had this illness since age 6 and they haven’t
actually gotten treatment and they’ve gotten way off track in their life and I can reduce
their symptoms in their 40s but I can’t give them back the 25 years or 30 years of their
life that they’ve lost. Even to increase access to our treatments, there are lots of
people out there who don’t even get our treatments 101 that we know work and also
to improve the delivery. For the patients of tomorrow I think we have a much more
ambitious goal and I hope to see it realized in my lifetime. You know we hope to
develop novel treatments based on a better understanding of the brain mechanisms
and really the goal is to prevent the development or progression of this illness. Now
to be successful in this research agenda, we really need everyone in this audience,
you know we need patients who aren’t satisfied with what they’ve gotten and who
advocate for research and who are our partners in coming into our studies and
helping us to advance what we know. We need clinicians who are advocating for their
patients as well and are not satisfied with what’s out there and who are opened to
using new things that are coming down the pipe. We need scientists who ask the
right questions and I think keep their patient front and center and don’t get lost in, if
you will, the minutia which we scientists can do. We need organizations like NARSAD
to fund us. NARSADs incredible role has been to fund pilot projects in young
investigators to jump start things, because it’s very hard to get funding from the
National Institute of Mental Health these days unless you have really powerful pilot
data. And we need family and friends like many of you who showed up today who
come to learn about these illnesses who are not scared to talk about your friends and
family about the fact that you have a child or a loved one with mental illness and that
you show up to learn about these illnesses and you support our patients and you
support the research effort. Thank you.
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Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
Thank you very much, we’ll take a few minutes for some questions. Yes sir?
<Q:> [INAUDIBLE] how [INAUDIBLE]
Blair Simpson, M.D. – Columbia – Associate Professor of Psychiatry
[INAUDIBLE] the questions were about DBT and CBT?
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<Q:> CBT and [INAUDIBLE]
Blair Simpson, M.D. – Columbia – Associate Professor of Psychiatry
Yes. So DBT, deep brain stimulation is one of the novel brain stimulation treatments
that have been tried and studied in obsessive compulsive disorder. [INAUDIBLE]
experts in this and they’ve shown that in highly repressed [INAUDIBLE] in the sense
that there may be a service and can benefit from this treatment. What’s interesting
though is in speaking to [INAUDIBLE] Greenberg who runs those studies, how many
people they turn away because they haven’t actually had really good cognitive
behavioral therapy. They haven’t had some of the standard treatments first. DBT
now actually has humanitarian approval, Holly might know even more details about
this than I, but has received humanitarian approval for use in OCD and my
understanding of it is that means it’s actually now paid for, I’m looking at you Holly, it’s
now I think reimbursable bySarah Lisanby – Columbia – Professor of Psychiatry
It’s clinically available [INAUDIBLE]
Blair Simpson, M.D. – Columbia – Associate Professor of Psychiatry
It’s clinically available in certain circumstances I think there hope was that that would
mean eventually, might actually lead to reimbursement. Having said all that, I actually
think DBS while a very interesting treatment and it will also improve our neuroscience,
it’s really for a very, very, very small selected people and while I think it’s important to
make it available, I also think it’s critical to make cognitive behavioral therapy as well
as first line medications widely available as well, because more people are going to
benefit from those. PTSD, there’s a whole program in our clinic on posttraumatic
stress disorder and maybe another year NARSAD will highlight that, you can do a
whole talk just on PTSD. The bottom line of it is, there’s a variance of exposure
therapy that is highly effective for OCD that is highly effective for posttraumatic stress
disorder and the recovery rates and the remission rates are even better than what I’ve
showed you for OCD.
[INAUDIBLE]
Blair Simpson, M.D. – Columbia – Associate Professor of Psychiatry
I’m sorry I realize I should say the question first so everyone can hear. It’s a very
interesting question. The person in the audience is pointing out that certain
antipsychotic medications can actually trigger OCD symptoms. And that hasn’t been
shown so much in randomized control trials but in case reports and the ones that
seem to do it the most are second generation antipsychotics like clozapine, Risperdal,
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olanzapine, all of these. It’s been reported in patients with schizo-effective disorder
and schizophrenia that you give these medications to treat the psychosis and then
what you get is an increase in OCD symptoms. There’s always an issue of well were
they there before and not noticed but I think there’s been enough careful look at this
that in some patients it seems like there might have been there a little bit beforehand
and now this medication has really increased them or they really weren’t there and
this medication seems to bring it out. And it’s a very interesting question that I would
love to study which is what is about, if you will, the brain of someone with
schizophrenia that this happens in and there are a lot of series but too much to go
hear now about it. I, the work that I know that’s been done on it is all sort of clinical
case reports and I haven’t seen anybody do biological studies on it because the
difficulty of doing the studies and getting funding has really been problematic.
Clinically what people say is, if that’s what you see, you give someone with psychosis
this medication and they suddenly get this flaring of OCD symptoms, you usually
reduce the psychotic medication and if that doesn’t work you try to add low dose
serotonin reuptake inhibitors. The question is whether cognitive behavioral therapy
could be done on those case has really not been studied and people have been
scared but I think maybe unfairly scared to pursue that.
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[INAUDIBLE]
Blair Simpson, M.D. – Columbia – Associate Professor of Psychiatry
Absolutely,
[INAUDIBLE]
Blair Simpson, M.D. – Columbia – Associate Professor of Psychiatry
Absolutely. We can stand up here and wave our hands about how these things work,
the answer is we don’t know. In fact there’s a whole literature out there, you can have
another NARSAD on this, the serotonin reuptake inhibitors, yes they might bind that
serotonin transporter but that’s not their mechanism of action. There are scientists
here at Columbia who are looking at neurogenesis and would argue that the effect of
serotonin reuptake inhibitors on depression and maybe OCD has absolutely nothing
to do with modulating the serotonin system. And your other point is well taken. It’s
not like any of these chemicals sit in isolation, they’re all interacting with each other so
of course if you shift the serotonin system, you have profound effects on dopamine
and glutamate metabolism and how this all works. The honest truth is we don’t know
and that’s why it is true, that that old clinical art of going slow and carefully and having
a clinician who’s really following you and trusting when you say I’m feeling worse, they
don’t say back to you oh that can’t be true but they’re actually, you know what, they’re
actually following you because what happens if it’s about a balance thing. You see?
And at least again, not to belabor it but in some of the cases that we’ve worked on
with schizophrenia and comorbid OCD, it seems like it’s a little balance thing about
how do you get them in balance and it’s not like there’s a ruler for that.
[INAUDIBLE]
Blair Simpson, M.D. – Columbia – Associate Professor of Psychiatry
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And the reality of is, the reason why we’re doing the serotonin imaging studies is
because if you will the serotonin and the- sorry the question is she’s exactly right,
which is the serotonin hypothesis has been around forever, it’s now out of favor. The
hypothesis that’s in favor now is glutamate. Ten years ago the hypothesis that was in
favor was dopamine. Here’s the problem from my point of view. It goes in and out of
favor on no data at all. You know it’s sort of like, what you have to do it seems to me
is collect the data. Now when I proposed the serotonin transporter study, did I
actually think I was going to find abnormalities? If I had just got my money, I’d say no
but I’d rather do the study and know it was no and go onto the next than just keep
debating whether it was this or that, not on data. So what I would say the truth of it is,
is again, right now glutamate is tops, so we do, we have a proposal in front of
NARSAD to go look at glutamate. Do I think that’s going to be the be all and end all?
I’d rather go get the data, don’t know if that helps you.
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Do you want me to stop? No, okay.
[INAUDIBLE]
Blair Simpson, M.D. – Columbia – Associate Professor of Psychiatry
I have heard of the Wolfman case with Freud and he has been re-analyzed as really a
classic case of OCD. More generally what I would go to and it always, I think it’s very
hard for families. When they go to one expert and one expert says X and they go to
some other expert and another expert says oh no, it’s not X, it’s Y. And you know my
heart just sort of goes out to you because you just want to sort of have an answer and
a treatment plan and you want to have a confidence in the people who are treating
your family member. I think sometimes it’s hard because these conditions evolve over
time and there’s a developmental aspect of it and they’re not always crystal clear and
so we have seen for example kids with very psychotic-like symptoms when they’re 12
that really keep evolving and it becomes very clearly OCD, so you know and yet at 12
it would have been very hard to know because what they’re telling you about is, they
feel like the devil is talking to them. Well it really turns out it’s a little kid whose getting
these intrusive harm images and doesn’t know how to describe it that way and it’s like
the devil is talking to him. Then there are also people who are comorbid, they have
both and there is a small subset of OCD patients who actually have a deteriorating
course who early on can look like OCD and then actually can become more and more
psychotic. I guess what I would say to you is I would feel, I would hope he would feel
confident trying to sit down with them and literally saying that this is very confusing to
me, how can you say one thing and now you say another, I really need this explained
to me. And I think if it’s confusing for you, imagine how it is for your poor son.
[INAUDIBLE]
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
Thank you.
[INAUDIBLE]
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
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I’m Jeffrey Lieberman and I have the honor of sort of succeeding Herbe Pardes as the
Chair of Psychiatry at Columbia and the Director of the New York State Psychiatric
Institute and I, before I took that position spent my entire career, about 25 years
working on schizophrenia research and specifically trying to understand how the
illness evolves, what is the underlying pathophysiology and then what are the
therapeutic opportunities for intervention that can maximize recovery and reduce the
morbidity of the illness. And what I’m going to do today in my talk, which I’m going to
go through in a slightly faster fashion than I would have otherwise because we got a
little bit of a late start and I don’t want to keep you too long, is to give you an update
on what’s happening with regards to treatment. Now, currently in the field of
biomedical research and including psychiatry and including brain disorders that we’ve
talking about, there has been tremendous emphasis and excitement about- there’s
the gentleman telling me please talk into the microphone so that the webcast can do
this. Okay.
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This is the Rube Goldberg approach to 21st century amplification. So the work on
genetics, the work on genetic mechanisms translating into etiologic pathogenic
processes which give rise to illnesses has really become kind of the major focus
which is going to lead us to the hallowed ground of personalized medicine. But, all for
that research, as elegant and as breathtaking as it is, ultimately will need to be
translated into treatment. Because treatment is where the rubber hits the road in
terms of being able to really change what would have happened to a person with a
given illness. So I want to tell you where we are with respect to treatment and
schizophrenia. And the question here is at this stage of our current therapeutic
capability, is recovery possible?
So this was the state of people who were unfortunate enough to have developed
schizophrenia circa the beginning of the 20th century and that was that the best they
could hope for was that there illness, once it had its onset and ran its course, really
without any kind of opposition from any effective therapy, which there wasn’t at the
time, what they would do would be to maintain people in a humane fashion in some
institution. And so this was people who were in their middle ages, middle-aged they
were not elderly but they were affected by the illness to the point that they could not
manage themselves in the general population independently. And so they had to be
maintained in an institution. And the reason for that is because the way the illness
evolves, even though it is different in each person is relatively consistent and that is
that people, even though genes may produce the predisposition to the illness and it
affects brain development, there is really a latent period in which the disease is silent
and it only begins to express itself after puberty, during a so-called period of risk
which is in adolescence and early adulthood. And when the symptoms merge,
persist, become severe enough and somebody is taken to a doctor for evaluation, a
diagnosis is made and somebody is said to have their first episode of psychosis, the
first break in the course of schizophrenia and what we’ve learned is that treatment
here at this initial stage is highly effective, high rate of symptom remission, good
prospects for recovery but no one, virtually no one who has a first episode, remember
this is teenagers or young 20-somethings who think they’re invulnerable, they’re at the
peak of their powers, when they get sick they don’t know what happens, they may be
treated and get better and they don’t think or they don’t understand this could be a
lifelong recurrent illness and after they get better, they take their medicine for some
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period of time, but then they stop and recurrences occur and as these recurrences
occur, there was a process in which there was a progression of the illness, that
produces a clinical deterioration of intellectual functions and also personality. Now
this process is one which isn’t inexorable and leaves like does Alzheimer’s disease or
Parkinson’s disease to complete disability but rather it leads to what is kind of a
chronic stable residual phase of the illness where people have persistent symptoms
and functional disability. As the illness wears on in this chronic residual stage, there
tends to be an increase in the degree of symptoms in addition to the psychosis, such
as the negative symptoms, the cognitive impairments and the greater difficulty in
being able to function whether it’s in the real world socially, vocationally or just
managing your independent living skills. Now, for this reason, that people who are
affected by schizophrenia are affected young, early, it does not kill you but it disables
you and you can live long lives, albeit with some disability; this means it turns out to
be an expensive illness. In a world bank study of the global burden of illness, it turns
out of all the illnesses in the age group of people from 15 to 24, schizophrenia is the
third most disabling and expensive disorder. And depression is actually the most
expensive. It’s only when you come to the fifth disorder that there is something that is
non-psychiatric.
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Now currently we have good treatments for schizophrenia, however we don’t
necessarily do the best job, an optimal job of implementing them. And this is an
example of what happens when the treatment which does exist but isn’t availed, the
person doesn’t avail themselves of it or it isn’t provided adequately occurs. This is a
story of a man named Nathanial Ayres who was the subject of a movie that recently
was released called The Soloist. How many people happened to see The Soloist?
Okay, well this was one of Hollywood’s better efforts when it comes to treating the
subject of mental illness. So Mr. Ayres grew up in Cleveland, Ohio. He was a
musical prodigy, he came to New York to go to school at Julliard and when he was in
school there, as a 19-year-old, he became a symptomatic with signs of schizophrenia.
He was diagnosed, he could not continue in school, he ultimately didn’t follow up with
treatment, he fell through the cracks, years later surfaced on the streets of Los
Angeles and was noted by a journalist there who dug into his story and found it
interesting enough to write a book about it and tell. But at that point he had already
been ill for 20 years, he was really beyond any significant degree of rehabilitation.
And I don’t know what his current circumstances are but he certainly has not even
come close to fulfilling what his potential was originally.
Now here’s another inhabitant of Los Angeles, like Mr. Ayres. Her name is Ellen Sax.
Now Ellen Sax represents sort of the other story, the other side of the continuum
story. This is a woman who grew up in Miami. She went to school at Vanderbilt. As
she was beginning college she began to have some changes in her mental
functioning, but it didn’t really disrupt her. She won a Rhodes Scholarship, went to
England. While she was studying there she had a full-blown psychotic episode, was
diagnosed with schizophrenia, was hospitalized, got good treatment, her family got
very much engaged, they were knowledgeable, encouraged her to stay in treatment.
She enrolled in Yale Law School, graduated and now is on the faculty of the Institute
of Southern California and has an endowed professorship and just won a McArthur
Genius Award. In addition to publishing her story as a book, called the Center Cannot
Hold; and that’s with treatment. So treatment does work currently, the important thing
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is providing it, as fully as possible, as necessary and providing it as early as possible.
So what we’ve learned since the introduction of antipsychotic medications, and the
various psychosocial therapies that I’ll talk about in a moment is that key element in
the therapeutic strategy of trying to mitigate the effects of schizophrenia is preventing
this from occurring, this progression of the illness, which leads to this, this chronic
residual end stage of the illness.
And the reason why it’s so important is because with longitudinal imaging studies,
using magnetic resonance imaging to evaluate brain morphology, over time as the
illness progresses, it’s been determined that there is a progressive loss of a small
amount of grey matter in the brain. So this is a movie of a serial study in which
patients were studied in their late teenage years and followed annually for five years
and you see the progression of changes in the brain from their first assessment over
time and in relation to healthy volunteer people of the same age. So the redder the
brain gets, the more of the grey matter is being lost over time. Now this is not a huge
amount, they’re not having massive devastation of the brain like would occur let’s just
say with Alzheimer’s disease but it’s about 1% to 2% per year, we see how this
progressively occurs. Now that’s what’s being measured on the MRI. What we think
is causing these images to occur is this.
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We heard before from Dr. Lisanby, and Simpson about the synapse, so here’s the
synapse in the case of schizophrenia, the presynaptic cell releases dopamine, that’s
the key neurotransmitter here. The other neurotransmitter that’s relevant is glutamate
and it usually stimulates these postsynaptic receptors, if there’s too much of it or if this
is somehow disregulated, it can over stimulate these receptors and potentially cause
some type of excitatory toxicity. When this occurs you get in effect, a loss of each of
these branches or these spines which is a synapse, and in effect when this occurs,
because of persistent psychosis or recurrent psychosis, you get a pruning of this
dendritic arbor and that is what the MRI is detecting and reflecting as the loss of grey
matter when this is quantified. So when that’s lost, our treatments which are good at
stabilizing the synapse, restoring balance of a chemical neurotransmission are not
able to restore the actual cell processes. They’re not neurotrophic, they’re not
neurogenetic, they’re chemical stabilizers. So antipsychotic drugs have become kind
of a mainstay of treatment. It’s not all that you need but it’s an essential component of
treatment. And we didn’t have those really until the latter part of the 20th century. And
the first one that was introduce was chlorpromazine; this was a drug that bounded
blocked dopamine at the dopamine-II receptor. Many other medications followed that
were chlorpromazine line in having this pharmacologic property, the ones that
asterisks are ones in which long-acting injectable forms of the medication were
developed so you could administer them weekly or bi-weekly or monthly. The next
real innovation node did not come until 1989 in the United States with the introduction
of clozapine. Clozapine also binds to the dopamine-II receptor but it has much less
affinity, it’s a kinder, gentler kind of antipsychotic drug, it’s not as heavy handed as the
dopamine receptor and it also acts with other neurochemical system receptors like
serotonin, like norepinephrine. Clozapine however had major side-effect problems,
mainly including its potential to cause agranulocytosis and as a result, many other
medicines were developed to be clozapine-like and these include all of these which
are currently now on the market and there’s one more that’s in the offing, about to be
approved this year called lurasidone. So we certainly are suffering from a lot of
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different brands. The problem is that these drugs are not so much different from each
other in therapeutic efficacy. Clozapine clearly is the most effective drug, and in terms
of the differences in efficacy between these drugs and these drugs is not a huge
difference. The major differences that occur are in the side-effects, not in the
therapeutic effects, the clozapine being the exception. And it’s a little bit ironic that
the drug that’s most effective is also the one that has the most side-effects.
So what can these treatments do? We know absolutely, positively, I mean you can go
to the bank on this, well actually that’s probably a bad metaphor these days, but you
can count on it that they suppressed psychotic symptoms, they prevent the recurrence
of relapses and they also, if you continue the treatment in a way that prevents
relapsing, they can prevent that progression, that loss of grey matter that I was
showing you before. What they can’t do is, they can’t alleviate the psychotic
symptoms in everybody. Some people, even though they’re better with medication,
still have persistence of the hallucinations, the delusions, the thought disorganization.
They can’t alleviate the negative symptoms, the cognitive impairment and they can’t,
when people develop functional disability, they can’t rehabilitate them and they can’t
regenerate lost grey matter. What we’ve learned in trying to develop more, another,
another, another antipsychotic drug in the hopes to really developing a silver bullet is
that there’s probably in the end going to be no influent for schizophrenia. No single
one medication. Schizophrenia will probably be more like cardiovascular disease or
hypertensive cardiovascular disease where you use multiple medicines that have
different mechanisms of action to control the different aspects of the illness. So this
will be a form of polypharmacy, multiple medicines. Now you’re probably saying, well
that’s not new, my son/daughter/husband/wife/me, I take multiple medications. These
are taking multiple medications because the one you’re on is not working well enough
so others have been added in the hopes of improving it without any evidence to show
that that’s really going to happen. We haven’t developed the appropriate adjunct of
medications to enable rational polypharmacy.
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What we need to do is to identify the targets that will enable us to develop drugs to
treat the illness getting the other aspects of the illness that the antipsychotic drugs are
not able to alleviate. And those targets are emerging from the studies that Dr.
Simpson was alluding to, you know the genetic studies, the studies looking at the
proteins which were the products of the genes that are identified as being associated
with the vulnerability to develop schizophrenia. And there’s a bunch of them that’s
been identified so far. This a small list; they are proteins which are involved in
different neurotransmitter systems and we hope that with the encouragement of the
academic research community, the pharmaceutical industry will develop compounds
for these. I have to say though at this point, one rather ominous development lately
which I hope, I imagine you’ve read in the newspapers or heard in the media, is that
as the pharmaceutical industry has retrenched in this current economic recession and
also amidst criticism about a variety of things in the media, they’ve selectively cut
back on their drug development efforts in brain disorders and particularly in brain
disorders that affect mental functions and behavior. So I don’t know where the new
drugs are going to come from because we desperately need the pharmaceutical
industry in order to develop these. One thing I’ll just add as sort of an editorial
comment is that as objectionable as we find the pharmaceutical companies behavior
in charging too much or in marketing or things of that sort, they’re not the tobacco
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industry. If tobacco was gone tomorrow, the world would be no worse and probably
better for it. If the pharmaceutical industry was gone tomorrow, we’d be in big trouble
Now here is an example just to illustrate for you how these new drugs should be
developed rationally. These are the targets. So the targets that I’m going to illustrate
for you is this, particularly the Gaba-a, alpha-2 receptor agonist and the way that this
comes, it’s easy for me to say isn’t it. My wife loves it when I talk dirty like this. So
the Gaba-a, alpha-2 agonist is the target that we want to try and develop drugs for.
So why develop a drug for that particular target. This is why. Within the brains of
people who have died who had schizophrenia, it’s been found that a type of cell, these
little inter-neurons are deficient. They are not there in the same number as they are in
people that didn’t have schizophrenia. Now these inter-neurons sit up here in the
cortex and they act on regulating these big, big cortical pyramidal cells which are
really doing the heavy lifting in thinking and in communicating with other parts of the
brain and telling you what to do, and making decisions about things and remembering
things. It’s these cortical pyramidal cells that are doing all the heavy lifting here. But
they are regulated by these little inter-neurons. The inter-neurons regulate them by
secreting Gaba onto these cells to stop them or start them from firing. So there’s too
few cells here in people with schizophrenia, leading people to suspect that that this
regulatory effect is somehow compromised or is diminished. And specifically, the
Gaba that is secreted here acts on a Gaba-a subtype, alpha-2 subtype receptor so
there is a variety of classes of these receptors. It turns out what these Gaba cells do
since you’ve got 100 billion in the brain, is to make cells fire in co-ordination so that’s
not a cacophony of noise, but they’re organized like an organized like an orchestra
and they are making music. And one of the ways you can tell that that is happening is
by doing these EEG recordings and looking at the so-called gamma bands, which is a
certain frequency level and that is a measure of cortical synchrony. How in tune are
these cells? Are they working together or not?
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And it turns out that the signal from the gamma band is lower in people in
schizophrenia and we believe its due to the deficiency of those Gaba-secreting interneurons. So if we can give a drug that will stimulate what these cells, because they
are not there, are not able to do, maybe that will enhance the neural synchrony and
also improve the function of the brains of people as reflected by cognitive tests. So
there was a study that basically test this hypothesis just this year and there was a
selective Gaba-a agonist and they found that it improved people’s memory functions
and executive functions. I’m sorry, I left out one slide but if I had the slide in, it would
show you the gamma band recording of the patient’s pre and post treatments and in
addition to improving their performance on the cognitive test measures, it increased
the strength of their gamma signaling. So this is how the new treatments are going to
be developed.
Now the other thing that we need developed in addition to these targets for the
selective proteins is we need treatments which can, those are good treatments but we
need treatments that can restore the grey matter that people have lost who are
already five, ten, twenty years into their illness- that are neurotrophic, neurogenetic
and are neuro enhancing and there is a variety of targets which compounds can be
developed that can be stimulatory that help reduce, the same kind of approach is
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being taken as anti-aging agents to try and enhance neuro-resilience and be able to
stimulate opposition to age dependent loss in brain grey matter.
So why don’t we get better outcomes from our treatments, from our patients given our
current treatments? Well one is that most people don’t stick with treatment for a
variety of reasons or we don’t encourage them aggressively enough. The second is
that we don’t combine with medicine the things that you need to provide because they
help and what I am talking about here are things like case management which is really
having somebody to basically be a life coach. To help that person with their day to
day living. How do you get your insurance paid? How do you make your
appointments? How do you travel to your appointments? How can you seek some
type of employment? How can you figure out how to get back into some kind of social
activity? How do you make friends? How do you dress? I mean the most basic
things. I need a life coach for a lot of my faculty but it’s not; I can give them pointers
but patients don’t necessarily get them.
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Other things they need, when they try and go back to school or go back to a job, they
sometimes need additional assistance than the school or the workplace provides
them. That’s called supported education and supported employment and there are
specialists that can do that. There are also forms of what are called cognitive
remediation, the psychosis can be suppressed but sometimes the parts of the brain
that are involved in mediating cognitive functions don’t come back as fast. But these
are not available in most clinical settings and they are not always reimbursed by
government or private insurance. And then of course, as somebody mentioned before
we have the real bane of many patients in this list which is substance abuse
comorbidity.
Now you know in some ways this is regrettable and is not our fault but in other ways,
there are things that we are not doing that we could be doing better. One is, is we
don’t use Clozapine enough. We should use Clozapine more. Only 5% of all people
who take anti-psychotic medications take Clozapine and it is clearly the best
medication in terms of efficacy. Second is we don’t use the long acting injectable
medications either and for people who forget to take their medicines or can’t be relied
on, these can be very valuable. The psychosocial therapies I mentioned and the final
thing that I want to just finish with is on early detection. This is the wave of the future
given our current therapeutic capabilities. It is for the future generations but it will
really change the face of schizophrenia. What we have learned is that the longer
somebody is sick before they are initially treated, the less good their chances for
recovery and their prognosis. The longer you are symptomatic and the more
episodes you have, the harder it is to get better. And if you treat people early, prevent
the progression and enable recovery and I think there is enough evidence to suggest
that the answer is yes so that the government is taking a chance on funding this stuff.
Here is an example that sort of illustrates how that can be the case. This is data from
a study that was comparing two different types of antipsychotic medications and it
used in addition to measuring the symptoms of patients, it looked at brain morphology
reflected by grey matter volume. So you take an MRI, you do a computer analysis to
segment it into the grey matter, the white matter and the fluid containing structures of
the brain and then you quantitate it volumetrically and what is seen is that if you look
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at 20 something-year-old kids who are young adults, who are followed for a year and
have three imaging assessments, they have up to 700 cc total brain grey matter
volume which is about average for a young adult and at that stage of life, there is no
age-dependent decline in grey matter such as I am experiencing even as I get greyer
hair. And it stays flat. For people with schizophrenia, same age, 22 on average, are
slightly smaller, maybe 15 cc, not that much, but over the course of this year, they
lose that 2% that I was referring to. So when we looked at it in terms of the two
different treatments, one treatment mitigated it whereas the other didn’t. Now we
don’t know whether it was the pharmacology that was better or whether people just
because it had fewer side effects stayed on this more and were more willing to take it.
But whatever the case, it indicates that you can prevent this loss and this deterioration
from occurring.
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This is simply a movie which illustrates as the red appears, it shows the grey matter
loss occurring and the relationship of these brain changes correlates with
symptomatic and functional outcomes, the more grey matter that is lost, the less
improvement in symptoms and in functional capability. So this has been a very
profound wake up call for people in terms of early detection and not wait till things get
really bad before treating. You can really stop the deterioration if you treat early and
in doing so, prevent this from occurring. But people have said, well usually we get the
chance to diagnose and treat people here but knowing that they frequently become ill
in a more gradual way and have this so-called prodromal phase of the illness, what
about trying to identify them there and stop the whole thing from beginning in the first
place. Well that’s a brilliant idea but easier said than done. Nevertheless, that’s what
the field is now doing. A strategy has been developed to identify people who may
have a family history of schizophrenia but even if they don’t and they have what are
mild symptoms, not diagnosable but mild, changes in their behavior, their mood, their
thinking, their cognitive functions and if you follow these people who are called
prodromal or at high risk, what you find is that over a one to two year period, about a
third of them will develop a full-blown syndrome of schizophrenia. Now that’s good
because these people are at higher risk so it’s like minimal cognitive impairment with
Alzheimer’s disease. However, 70% of them do not. These would be called false
positive cases, people who are identified as being at risk but really haven’t developed
the illness. So this poses a problem in terms of putting a label on somebody and if
you are providing them a treatment, if it has side effects, you are exposing them
unnecessarily. Nevertheless, there have been some studies to see if treatment can
prevent conversion to the full psychotic episode and the treatments are effective if you
use an anti-psychotic drug but if you use an anti-psychotic drug, you are exposing that
70% to an anti-psychotic drug unnecessarily. So people have been looking for less
invasive, less heavy-handed treatments and one of them, that’s been studied very
recently was 3-Omega fatty acids which I happen to take as do many people, for
cardiovascular reasons.
So this was an interesting study in which people who met these prodromal criteria
were assigned to either take 3-Omega fatty acid or take a placebo pill and the
conversion rate was about 20% in the placebo group and very low in the 3-Omega
fatty acid. Now this is a very interesting result but we need to replicate it before I’m
willing to say you can take it to the bank or at least you can bet on it. We don’t know.
But this is the strategy. Nevertheless, the thing that would make all of this a lot more
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efficient as well as safer is a diagnostic test. The lack of diagnostic criteria to identify
people who are at risk is a huge limitation. It is like, let me give you an example, it’s
like suppose you were trying to diagnose somebody who is having a heart attack
without an EKG or without being able to do a blood test to see if they had elevation of
their CPK enzyme and you said to them, what’s the problem and they said, well I have
chest pain. What does it feel like? It’s like a burning in my chest and you say, well did
you eat something? No, no, I didn’t eat anything but it’s a burning in my chest, it’s
unpleasant pain, I’m perspiring … and you’re not sure if it’s a gallbladder, you’re not
sure if its heartburn, you’re not sure if it’s a heart attack. That’s the way medicine was
before we had the EKG. That’s where psychiatry is in trying to diagnose the prodro.
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So what can we do? Well there are a number of diagnostic measures that are
currently in development that look very promising. I will just show you one because
we’re doing this work here at Columbia. So this work was done and I’ll just comment
that the work was supported by NARSAD, by Scott Schoebel and Scott Small and
they used a magnetic resonance imaging technique. They hypothesized that, they
had already done this work with Alzheimer’s disease and showed that you can
diagnose Alzheimer’s in people who have mild cognitive impairment by looking at the
hippocampus and seeing the degree of metabolic activity in this. And so they applied
this to schizophrenia which also involves neural circuitry and they hypothesized that
since schizophrenia is known to involve the hippocampus from post mortem studies
that they would be able to detect the earliest signal of overactivity leading to psychosis
in one of the sub regions of the hippocampus. And in Alzheimer’s disease, what they
had shown was that, and this is just a magnification of the hippocampus right here
which has been color coded to show the degree of metabolic activity. You see, here
is your healthy age-matched control, so these are 70-something-year-old people. We
see the hotter it is, the more red. The colder it is, the more green or blue and if you
look in this region, around the cortex, you see it’s pretty hot and red here in this
control group, in the Alzheimer’s group with minimal cognitive impairment and you see
this is a colder activity so it’s hypometabolic.
So here are the schizophrenia patients. So these are your healthy controls. These
are people with the first episode of schizophrenia, and these are the prodromal
patients. And what you see here in the CA1 and subicular regions of the
hippocampus you see this increased activity; in the controls, it’s not present.
Prodromals are intermediate between the controls and the schizophrenia patients. So
we think this has the potential to be a biomarker for identifying patients. Right now
when we diagnose schizophrenia, we can do nothing for people before they are
symptomatic and even when they are prodromal, we have only a 30% accuracy
rating. We have to wait until they have the full-blown symptoms before we know that
they have the illness and can treat.
Again, contrasting this with cardiovascular disease which is at the stage that we are
some half century ago, the family history, you can do things to evaluate risk, you can
take interventions that are preventative and are different from what you would use
after somebody develops coronary artery disease and when you have symptoms you
can do more things to evaluate with a level of certainty that they have the illness. So
this is where psychiatry is moving and this is how it is being applied to schizophrenia
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and one of the most important ways that they will serve that purpose is in the area of
early detection and intervention, particularly in the prodromal phase.
So let me just conclude by saying that the first person at the presidential level to really
focus attention on mental illness was Rosalyn Carter and she was asked recently
what’s the biggest change in mental health care that’s occurred from when you first
started this until today and she said, it’s that recovery is now possible, whereas then
people were pretty much written and the notion of recovery is something which is very
important within mental health care because it says that no matter where you are in
the course of your illness, there is always hope that you can have a meaningful life,
even if it doesn’t mean that you will achieve a full remission of your illness or cure and
that is what I think we are working towards with the idea of optimizing the use of
medication, of psychosocial adjunct treatments to try and foster the greatest level of
recovery for people, at the same time we are trying to develop new approaches that
will help people who have been ill for some period of time but also prevent the illness
in future generations from developing it.
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So our current model for treatment, knowing what we know about the course of the
illness is that we have this deterioration which leads people to this chronic residual
phase. Treating early can prevent but in lieu of that, doing all we can with what we
have in order to foster recovery. Thank you for your attention and again, thanks to
NARSAD for all they have done.
If we could have the lights up, thanks.
I’m going to take just a couple of questions and then we are going to invite Dr. Herbert
Pardes to make some concluding remarks for the session. Yes sir in the back.
<Q>: [INAUDIBLE].
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
The question is, is Dr. Hoffman studies with RTMS, yes Dr. Lisanby is doing those,
right here at Columbia. Yes sir?
<Q>: [INAUDIBLE]
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
No, she had several episodes. She had several episodes. She had, I mean I think
what made the difference for her was that she remained in treatment, she had good
support from her family and she also got married and had a very supportive husband.
You can not overestimate the importance of having a healthy committed personal
relationship with somebody. Yes ma’am?
<Q>: [INAUDIBLE].
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
Did you say?
<Q>: [INAUDIBLE].
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Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
Your question is, is there a study of medications that don’t cause side effects?
<Q>: [INAUDIBLE].
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
You mean other side effects?
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<Q>: [INAUDIBLE].
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
I would say it’s almost impossible that it had anything to do with the thyroid cancer. I
mean, psychotropic medications can produce an array of side effects and one of the
most common of the new anti-psychotic medications as well as mood stabilizer
medications is weight gain. But thankfully has not been a side effect of any. The
most serious thing along those lines has been the agranulocystosis associated with
Clozapine. Yes sir?
<Q>: [INAUDIBLE]
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
Yes, I will. Yes sir?
<Q>: [INAUDIBLE]
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
Well, as a matter of routine, it’s not done widely, certainly not uniformly. I’m sorry, the
question was family education, how widely is it carried out in treating people. And the
answer is, it’s not done widely but it is incredibly important. It frequently occurs
somewhere in the course of the person’s illness. You know, ideally it should occur at
the beginning. Eventually, you know, curious, persistent knowledgeable family
members get the answers they are looking for but they often have to really dig for it
and go to multiple sources to get it. It should occur right at the beginning. Part of it
has to do with the fact that you know for a long time, the stigma of mental illness,
people didn’t want to know, doctors didn’t want to tell them. There was also this
notion, particularly with analytically oriented psychiatry, you don’t talk about the
diagnosis with the patient, that’s all in the past. You know the diagnosis should be
discussed because if you know what is ahead of you, then you will have a much better
understanding of what the treatment options are and how you should make your
decisions. Yes sir?
<Q>: [INAUDIBLE]
Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
And so the question is how do you encourage the use of treatments that we know
could improve things like Clozapine and long acting injectables, particularly with
health care reform reducing reimbursement? That’s a good question. Dr. Pardes is
President and CEO of the largest Health Care system in New York and the 6 th largest
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NARSAD Webinar
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in the country and he is after having presided over the research enterprise of the
NIMH and now is worried about sort of the practice of medicine and how you influence
practice by putting the economic incentives in place so perhaps he will speak to that
as well. I think that’s the big challenge because you can have all the knowledge in the
world but if you don’t use it, it’s not going to do anything. So we have to incentivize
doctors through reimbursement mechanisms to use these things. Also make patients
aware of it so that they can ask even if they are not offered it. Yes ma’am?
<Q>: [INAUDIBLE]
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Jeffrey A. Lieberman, M.D. – NARSAD – Chair of Psychiatry
Boy, that is one of the biggest, biggest problems. If I could invent a pill that could
create insight … Well first I’d give it to teenagers but after that I would give it to my
patients. Maybe I would give it to my wife first. Don’t tell her I said that Connie. But
that is a huge problem. We have on our faculty, Dr. Xavier Amadore who this has
been his focus, which is the lack of insight into illness and he believes it’s actually part
of the cognitive disability which makes people, an incapacity to sort of absorb this.
We don’t have the solution but the approach that we take is a very aggressive
approach, you can’t take no for an answer. You have to find ways to encourage
someone to participate in treatments and you have to be very persistent about it and
the treatment needs to be multi-elements, it’s not just medication, it’s not just
psychotherapy, it’s engaging somebody in some group activities. It’s having them
work with cognitive remediation and in this way, they can then start to see the
progress they’re making because their lives change and that may have rewarding or
reinforcing effects but you can’t just say they don’t to do it, I’m just going to leave them
although it’s very hard because frequently you have to do things against their will. I’m
afraid just in the interest of time we’re going to stop here for questions but as I said,
we will remain here afterwards if anybody wants to come up and ask us. It’s a great
pleasure and honor to introduce Dr. Herbert Pardes to come up and to offer some
summary and concluding remarks. Please welcome Dr. Herbert Pardes.
Herbert Pardes, M.D. – NARSAD – President
You know listening to these rather outstanding presentations and trying to take stock
of mental illness, vintage 2010 is really quite a challenge. Let me just say the kind of
interesting starting point, my first contact with psychiatric illness was about 50 some
odd years ago and the contact involved going to a state hospital where I found naked
men in isolated rooms smearing stool around the walls and I offer that just to say that
as formidable as the situation may look there has been quite a change. Now what
you are hearing is a number of outstanding investigators and as you may know,
Columbia, the New York State Psychiatric Institute, New York Presbyterian Hospital
as Jeff said constituted an enormous concentration of psychiatric research, really
have very large scale programs and one of the things that is interesting in the mid
80s, I had been NIMH, Mental Health Institute Director in Washington for the last six
years, we did a study and found that there were very few research centers around the
country that were doing very much in the way of mental illness research, you had
maybe 5 or 10 with any program of consequence, nothing like - you had Columbia
and a few others like that. And today, that’s changed considerably so that psychiatric
research in any given medical center is usually number 1, number 2 or number 3 in
terms of size.
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Now, the point that it’s large is not the point. My point is that there has been an
enormous change over some decades in terms of building more of a psychiatric
research enterprise and one of the other things that is interesting is that there is
considerable cross over between non-psychiatric research and psychiatric research
so that many of the techniques that are promising in medical fields other than
psychiatry are also being picked up in psychiatry and you heard reference to them in
many ways, looking for targets, early identification, imaging – imaging has been one
of the extraordinary developments over the last 10 to 20 years and while I can assure
you that those of us who are clinicians as well as people who are patients are
frustrated by how long trying to get good answers takes. We still recognize that there
are a constant bevy of new techniques that emerge that offers us ways and hope in
terms of trying to address these diseases.
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Now let me just relate NARSAD to that. Because NARSAD is a rather remarkable
enterprise. It is all really generated and developed by families who often have or
almost always have psychiatric illness that they know in their own families – a child, a
relative, a brother or sister, a father and NARSAD has both been extraordinarily
successful in developing an additional arm along with the NIMH but also doing a few
things that the NMIH, the National Institute of Mental Health have greater difficulty
doing. So what do I mean by that? First of all, NARSAD made a decision early to
have the widest possible reach with regard to young people. So each year, hundreds
of new people are given support in order to develop and sustain their research
careers. You may know that given the tightness of funding, many young people find it
difficult to get into and then stay in research. So NARSAD fills the gap I think rather
nicely. Second, NARSAD is interested in maximum creativity. So we look for projects
that may be a little bit unusual. That represent ideas that might not make it through
the structured reviews of the federal government. And we also try to entice scientists
no matter whether they are in psychiatry or in any other field to come into the field and
we have been rather successful with that. In order again to get as many possibilities
going as possible.
What is impressive, again harkening back to the presentations of these three
outstanding professors, is that people have become aware of how frequent psychiatric
illness is. You say Jeff’s reference to the leading financial expenses with regards to
illness and also that reflects also the leading illnesses in terms of compromising
people’s daily function. It is extraordinary. Psychiatric illnesses constitutes some of
the most frequent and that helps us. It helps us because this is not an easy issue. As
you well know, many in this room have worked at it. There are many people who by
virtue of the fact, they are either inattentive, want to ignore it, want to deny, will usually
put psychiatric illness down at the bottom of their priority list in terms of the availability
of resources. And so there needs to be an army of people who promote it, because if
you don’t, it doesn’t get done. And there have been some very impressive examples
over the years. In fact, very recently, I imagine some of you may know but you should
know that the extraordinary attention that has been given to autism in the last several
years may be due to a number of people, but two of them, Bob and Suzanne Wright,
have been extraordinary. He was the head of NBC and they have simply given an
enormous focus and they have been there, I can tell you, influencing the government
in terms of where their priorities for funding should be. That argues that citizens can’t
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take this for granted but have to be activistic and if you care about psychiatric illness,
you better make your voices known and you better also try to get as much support as
possible.
There was a reference made to the Obama administration and also the health reform
plan and that could take us another day and half to discuss all the implications. The
comment though, it was questions and answers that I heard [INAUDIBLE]. I am not
aware of things that would necessarily in a discriminatory way, make psychiatric
treatment less available than non-psychiatric treatment. I don’t think this
administration is inattentive or unconcerned about mental illness. I do think that what
we may need is another commission on mental health because the mental health
system in this country, as far as I’m concerned is completely broken but when you talk
in terms of allowing or trying to support people being reimbursed for getting mental
health care, I think there there has been some distinct improvement and that has not
necessarily something that you can credit to any one particular legislator but there
have been a number who have been rather effective in this and also a number of
advocacy groups that have helped. So my feeling is that the story on reimbursement
and parody is much better today than it was years ago. That doesn’t nay-say the fact
that there may be concerns that come out of the reform plan of a variety of sorts.
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One of the things that is going to come out of the current administration is a big focus
on what is called comparative efficacy of treatments and you are going to see a lot of
studies done to say which treatments really do better and to try to discourage the
generation of treatments which offer little in the way of advantage but tend to absorb a
lot of the resources of the pharmaceutical industry. I think Jeff also made a very
important point about the pharmaceutical industry because it is easy to try to find
villans and they often are targets. But they play a critical role in generating new
treatments and it is somewhat worrisome, both in psychiatry and also as to where
exactly the pharmaceutical companies are in terms of helping the country generate
more treatments.
Well there is much to be said and the afternoon should come to a close. Let me leave
you with this. I have watched this and I have been involved in it for a number of years
and I would say that the picture today, even though it moves slowly is a million times
better than it has been over the past years and decades. And you have got a lot of
bright people, and NARSAD again is a factor in trying to stimulate that, trying to work
on better answers and better answers don’t necessarily mean immediately cures.
Cures are tough. If you take a look at many of the other illnesses whether its
hypertension or diabetes, we often do better, we improve by steps, even in
cardiovascular disease where there has been sensational improvements, there is still
a lot of heart disease. The basic pathophysiology of which we can’t quite grasp and
the treatments for which are still better but not perfect. So I would hope that you
would come home from today, first of all appreciating that you have got some very
outstanding minds working on trying to solve these treatments and find better
exploration for the disease and treatments for things that concern us all whether it is
you, your friends, family, etc. Second, not only is the government a potential help and
there we should be evocative as we can in making sure that they pay attention to
psychiatric illness, but third that you have got an organization like NARSAD working
with an outstanding group of academics like the people at Columbia and many other
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universities around the country, psychiatric institutes who are working on these
problems. I believe with the investigators who spoke today that you are going to see
constant improvement. Many of these treatments that you saw today, didn’t exist 10,
20, 30 years ago. I can tell you one other period I experienced as a young
psychiatrist was the period when we had 600,000 people in psychiatric state hospitals
around the country and people were revolving from state hospital to municipal
hospitals and going around and around when the only treatments we had were to
simply put them in the hospital for a few days. We had all kinds of shock treatments.
The shock treatment is much better today but there was a kind of accepted use of
shock therapy at one point back in the 60s. I think that was designed to keep the
electricians in business. But now you see quite a range of treatments, a focus on how
to figure out new targets for early identification, combinations of treatments, different
kinds of treatment and that we should certainly encourage.
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So, I want to conclude by asking us all to thank three outstanding investigators for
their presentations today. I think they did a great job. And most important, each and
every one in this room I’m sure has done something and will do and can do more to
advance this fight. And we all work at it in whatever we can. I do want to say that to
embarrass Connie and Steve Lieber completely. What they did was having the
experience of a relative in the family who had serious illness, they threw themselves
into this and I have never seen more dedicate people working on trying to find better
answers and better treatments for psychiatric illness and what I think they have done
with NARSAD is a national example which is absolutely remarkable. So let’s thank
them.
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