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					                                   MENTAL HEALTH RESEARCH SYMPOSIUM

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          Mental Health Research Symposium
          Palm Beach, FL
          March 6, 2010

                  BENITA SHOBE: Good morning. Good morning.

       (Laughter) Let’s hear that energy. Thank you so much for being

       here. My name is Benita Shobe, and on behalf of the board of

       directors from NARSAD and our staff, it is really a pleasure to

       welcome you here. It’s very nice to see just such a wonderful

       crowd, and you’re indoors with us rather than outdoors in this

       beautiful weather.

                  Joining me on stage in just a moment, or taking my place

       on stage in just a moment, is Dr. Jeffery Lieberman, as your

       moderator today. There are so many amazing things that could be

       said about Dr. Lieberman. We could share his extraordinary

       academic credentials from highly respected universities and

       medical institutions. We could share elements of his leadership in

       his current position at Columbia University. We could share the

       many prestigious awards, and honors, and recognition that he’s

       received from his peers and other organizations worldwide. And

       we could certainly share the very real pride that we feel at
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       NARSAD as he serves so generously on the Scientific Council.

                  We have shared all of this in this program book, so I’m not

       going to repeat everything that is in this program book. I hope that,

       at your leisure, you’ll take the chance to read everything that’s in

       there and learn more about all of our absolutely wonderful and

       world renowned speakers. As I turned the podium over to Dr.

       Lieberman, we feel it’s important to share what you won’t read in

       the program book. Dr. Lieberman, and certainly our other

       presenters represent the best, and the brightest, and the most

       hopeful researchers in this field, in the world.

                  He also represents the extraordinary commitment and

       generosity of spirit characterized by so many, or frankly, all of our

       NARSAD funded researchers. They share with us, around the

       country, many times, opportunities to talk to folks such as

       yourselves, to prospective donors, to people who are interested in

       the field, and we certainly appreciate all the free time that they give

       us. They give, ultimately, to you.

                  We’re so proud of our partnerships and grateful for the

       time and focus that he and so many others freely give to NARSAD;

       but again, most importantly, to you, the people that we ultimately,
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       through all of the efforts that we make at NARSAD help to serve.

       So please join me in welcoming our highly respected moderator,

       and our friend, Dr. Jeffrey Lieberman.


                  JEFFREY A. LIEBERMAN, M.D.: Well, thank you very

       much, Benita, for that wonderful introduction. Let me just echo

       your remarks by saying, on behalf of myself, my colleagues here,

       who are on the program today, the scientific research and

       academic psychiatry community in the country, we really welcome

       you to NARSAD, and we really look forward to working with you

       and your leadership in assuming the role that you have in what is,

       for us, an incredibly important, an essential organization, and one

       that, for the United States, is really of historic importance. So

       welcome. Thank you. And we look forward to working with you for

       many years to come, very successfully.


                  JEFFREY A. LIEBERMAN, M.D.: It’s great to see

       everybody here. This is like a same time next year relationship

       that we have. This is what, now, seven years that this conference

       has been ongoing? And it’s fabulous.
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                  JEFFREY A. LIEBERMAN, M.D.: Benita was, I think,

       being too gracious by saying it’s an imposition of our time, and we

       give of our time to do this. The reality is, we love to do it. And it’s

       not just to come down to Palm Beach and get away from the winter

       weather in the north, because that’s where we come from, but it’s

       because this is such a wonderful thing to participate in. When

       NARSAD asked us to go talk at various types of conferences or

       symposia, different parts of the country, we’re eager to do it

       because it’s something that we can do to support the organization.

                  More importantly, we really get a charge out of interacting

       with you, because this is the reason why we do what we do, to be

       able to help people make their lives better, and to get this kind of

       feedback to be able to provide the information directly, to get the

       stimulation of our very probing, sometimes very aggressive and

       inquisitive questions, is something that’s incredibly enjoyable and

       gratifying. So we’re glad to be here, and to just turn the typical

       phase a little bit, and usually people say we can’t go on meeting

       like this. In this case, we can go on meeting like this, and we

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                  This is really a fortuitous time in the field of biomedical

       research and psychiatry, mental health care, because the

       momentum of the science of the talent that are coming into the

       field is like never before. We are really poised to make rapid and

       accelerated progress. We don’t know exactly what the milestones

       of the breakthrough that are going to advance the field and change

       the way in which care is provided, but we know that they’re

       coming, and they’re going to be coming faster than every before.

       In large part, the rate limiting factor on all this is just resources,

       how much money our government gives to the NIH, which gives to

       the NIMH, and the other institutes which fund brain research, and

       how much money organizations like NARSAD can raise.

                  In mental illness, because of its historic kind of neglect,

       second tier status, being shrouded in ignorance and stigma, we

       didn’t have any private sources of support for research. We didn’t

       have the American Cancer Association, American Heart

       Association, the Juvenile Diabetes Foundation, the Muscular

       Dystrophy Telethon. We didn’t have things like that. And then

       came NARSAD, and NARSAD really has changed all that. There’s

       so much more that can be done, because there’s still a
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       tremendous, unmet need in terms of people who suffer from the

       variety of mental illnesses and don’t get adequate treatment. So

       we are really poised to do it. All we have to do is figure out how to

       deal with the political situation, the healthcare reform issues and all

       that stuff, that thankfully, I’m just a pointy-headed scientist. I don’t

       have to worry about those political and policy issues so much.

                  We really have a phenomenal program for you today. It’s

       a program which is really rich, but also diverse. Psychiatry and

       mental illness really deals with brain disorders that affects the part

       of the brain that are involved in controlling mental functions,

       cognition, perception, emotional regulation, and behavior. The

       topics that we have selected today to present to you on reflect a

       spectrum of these conditions, and they’re going to be delivered by

       some of the leading scientists in the world in these respective


                  We have four speakers, including myself, who come from

       some of the best institutions in the country, Yale, Columbia,

       University of Pittsburgh. And the way we’re going to do this is,

       we’re going to have each speaker present for 20, 25 minutes, and

       then we’ll have about 15 minutes for questions. We going to do to
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       talks, and then we’re going to take a break, and then we’ll resume

       for the other two talks, and then afterwards I think I will be able to

       remain for a short while to answer any questions. Our first

       speaker, Dr. Krystal, has to catch a plane to be somewhere else,

       so he’s not going to be here at the end of the program, so you’ll

       have to ambush him before he gets out of the convention center if

       you want to ask him something specifically.

                  Let me just say that there’s also an evaluation form that

       was given to you, or is available at the desk out there. Please, it

       helps us to know what was good and what could be improved

       about the program, so take the time at the end to fill it out and to

       leave it at the desk.

                  So without further adieu, it’s my pleasure to present a

       friend and distinguished colleague, Dr. John Krystal. Dr. Krystal

       has been for, throughout his career, a leader researcher in a

       variety of areas, including substance abuse, schizophrenia, and

       also, on the topic that he is presenting on today, which is emotional

       trauma and stress disorders, which is very much in the news lately,

       particularly because of the military, particularly because of some of

       these visible public violent events that are impelled by stress that
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       people have experienced.

                  Dr. Krystal is the Robert McNeil Professor of Translational

       Research and the Chairman of Psychiatry at Yale University

       School of Medicine. He’s going to speak on new insights into the

       neurobiology of PTSD. So please join me in welcoming Dr. John



                  JOHN H. KRYSTAL, M.D.: Thanks. Let me just echo

       what’s been said about NARSAD. So I’ve been a member of the

       NARSAD Scientific Council for a number of years, and I have

       received research support from NARSAD, which came at very

       important times in my career. Now, as Chairman, I see that we

       depend, we don’t just value, but we depend, as a department of

       psychiatry, on the support of NARSAD to help our most vulnerable

       group of scientists, the young investigators, just getting started in

       their career. We depend on NARSAD to help them to get their

       start, because it’s very hard to support a beginning research

       career. So I thank all of you for coming. Today, I’m going to be

       talking about stress, resiliency and PTSD, building on what we now

       know of PTSD as a brain disorder as well.
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                  So I’m sure everybody here has experienced stress in

       your life. Usually the stresses that we face invigorate us. They get

       us activated. They focus our activities, and they make life exciting.

       But very often, even in the day to day lives that most of us lead,

       that stress can easily turn into distress, where we feel

       overwhelmed and where we start to feel badly.

                  What happens when the stress that we face is not just the

       everyday stress, or even the extreme, the uncomfortable everyday

       types of stresses that we face? For example, what about child

       abuse, child maltreatment and neglect? What about sexual

       assault? What about genocide? And what about war? And

       combat is a very prominent and powerful type of traumatic stress

       that is affecting our country right now, as we have so many soldiers

       in Iraq and Afghanistan. This is really the starting point for where

       our work starts. We’re part of the Department of Veterans Affairs

       National Center for PTSD, which was the first multi institutional and

       multidisciplinary research initiative ever launched in this field of

       research. I happen to direct this research division.

                  PTSD is a complicated disorder. In other words, it’s not

       just one symptom. Many people who have been exposed to an
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       extremely traumatic life event will forever after have very vivid

       reexperiencing of the event, either in the form of intrusive thoughts,

       daydreams, nightmares, and then the most extreme cases, they

       can feel like they are reliving aspects of their earlier trauma. We

       call that flashbacks.

                  When people are thinking about, or exposed to reminders

       of the trauma, they can get very hyperaroused. They can shake,

       they can startle. Their heart can race. They can feel very irritable.

       That can be a problem. Then, another aspect of PTSD is

       depression-like symptoms, where people feel emotionally numb.

       They have trouble experiencing pleasure out of their usual

       activities. They tend to avoid situations where they may have to be

       exposed to reminders of the trauma; so that we think of PTSD as

       being involved in reexperiencing, hyperarousal, and avoidance.

                  Now, I’m going to present now a very simple model that

       gives me a framework for in the 20 minutes or so that I have with

       you today to very quickly go through some of the thoughts that we

       have about how it is that people develop PTSD, and just the

       beginnings of some of the ways that can help us to think about new

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                  We think of people, as Dr. Weinberger in the movie talked

       about, as having a certain genetic attribution that affects how they

       react to various life events. And they have certain life experiences

       that shape the way they react, so that when they’re exposed to an

       extreme stress, that that helps to determine the pattern of their

       response to that particular stress. They’ll have a neural response

       to that stress, in other words, the way their brain reacts to it; and

       then the way they think about it, their emotional and subjective

       response, all of which was extremely important for shaping the

       impact of that stress on them.

                  In the context of an extreme life event, you’ll see,

       subsequently, among people who are on the path to PTSD,

       problems regulating alarm or arousal. You’ll also see problems in

       coping with day to day life. We call that, for the purposes of our

       discussion, a failure of resilience. They’ll start to react to cues and

       things which are normally completely neutral, and not very

       significant to them, will start to react to these neutral reminders in

       very powerful way, which is an illustration of their conditioning or

       learning of fear or stress reactions. Then, if the reaction is strong

       enough and goes on long enough, they’ll develop these depression
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       symptoms, numbing, which may be associated with some negative

       effects on brain structure as well as brain function. That cluster of

       biological processes is what we currently understand to be the core

       of post traumatic stress disorder.

                  I’m going to start by talking about the alarm dysregulation.

       This is a story that really goes back to the turn of the 20th century,

       where a scientist named Walter Cannon discovered that if you

       activate the sympathetic nerve system, the system in the body

       that’s involved in releasing adrenaline and noradrenaline, that you

       evoke something called the fight-or-flight response. So that the

       stresses affects the brain, but it’s expressed in the body through

       the release of a variety of hormones and chemicals, and he in

       particular studied adrenaline and noradrenaline.

                  So when we were establishing our research center, we

       wanted to ask the question, how can we show that this chemical

       system in the body, the adrenaline or noradrenaline system, is in

       some way connected to the experience of post traumatic stress

       disorder? What we tried to do was to activate the adrenaline

       system in the brain and the body by giving a drug that prevents the

       noradrenaline system from turning itself off. The drug that we
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       administered is a drug called yohimbine. It blocks a particular

       receptor target called the alpha-2 adrenergic receptor, right here,

       which normally turns off the adrenaline system once it’s activated.

                  When we gave yohimbine, what we showed in chemical

       measurements was that the adrenaline system was activated.

       This is what happened. We had given yohimbine to many different

       groups of patients, people with panic disorder, people with other

       anxiety disorders, people with depression, people with

       schizophrenia, and people got a little uncomfortable, but we saw in

       PTSD a very unique and distinct thing, and, illustrated here.

                  We would be infusing the yohimbine, and the person in

       this case started to seem kind of jittery and agitated, and started to

       stare at the wall. I said, what’s happening? And the patient said,

       the helicopter’s going down. I saw the flash of light and the smoke

       trail. It’s crashing. I can hear it. I can smell the smoke. And he’s

       pointing to a blank wall, in a very quiet room. We had never seen

       this before. And this was part of one of the ways that we could

       show, and this happened over and over again, different versions of

       it, of course, and it was one of the ways that we could show that

       activating the noradrenaline system in the body was connected in a
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       very direct way to the signs and symptoms of post traumatic stress


                   So out of this work came a couple of basic ideas, that

       some PTSD symptoms were related to a problem in turning off the

       adrenaline system. And so it raised, in our center, the question

       about whether the ability to turn off the adrenaline system could be

       related to the ability to cope with stress. And one of the very

       interesting areas that we were drawn to, based on the interest of

       one of our colleagues, Ann Rasmusson, now at Boston University,

       was a more complicated idea about what noradrenaline neurons


                   As I mentioned, when stress comes along, the

       noradrenaline neurons get activated. That noradrenaline stimulates

       the receptor targets for noradrenaline in the brain, and you get the

       fight-or-flight response. But noradrenaline neurons also release

       other substances. It turns out that these nerve cells can release a

       variety of substances, and we’re just beginning to learn about how

       that colocalization of substances in the nerve cells influences

       behavior. The other substance that we were interested in was a

       substance called neuropeptide Y. When neuropeptide Y release
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       and stimulates its receptor target, it turns off the stress response,

       so the same neur(?) cell is stimulating a stress response, and

       responsible for helping to turn it off at the same time.

                  So we had a clue, but through genetics, that the

       neuropeptide Y system might be involved in the ability of people to

       cope with severe stress. For example, we found that a gene

       variation, or polymorphism in the gene that codes for the

       neuropeptide Y formation was associated with the vulnerability to

       post traumatic stress disorder.

                  My colleague, Andy Morgan, and Steve Southwick, and

       Dennis Charney, then were looking for a human laboratory that

       they could use to see whether some of these chemical systems

       were involved in the coping with stress. We began to work with the

       Special Forces Training Programs where they do some pretty

       extreme things in the training process. What I’m showing you here

       is a process in the Navy Seals training where they bind their arms

       together, attach them to weights, throw them in the pool, and wait

       for them to pass out. And here is somebody who is okay with that.

       I would not be okay with that. (Laughter) He seems to be okay
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       with this. Here is someone who looks more like what I would look

       like in that circumstance.

                  When they do that, when they bring them out, the

       resuscitate them, and then they say, you know, this training is

       really tough. You don’t want to do this. You really want to drop

       out. And the tough Navy Seals, they say, thank you, sir. I want to

       do it again. And they do. And they do it. They have to do this

       more than once. So this would seem like a pretty good stressful

       situation to study in terms of how people did or did not cope.

       People like me would have said, you’re right, I don’t want to do this

       again, and I think I’ll do something else, thank you. (Laughter)

                  So if we look at the noradrenaline and the neuropeptide Y

       system in these Navy sailors, what we found was something, I

       think, very interesting and very important, which is that the

       adrenaline system, the stress response system, is activated very

       strongly in the Special Forces soldiers. In fact, more strongly in the

       Special Forces soldiers than other people who, for good or for bad,

       had to go along in the same kind of training program.

                  What was striking, though, is if you look at the

       neuropeptide Y, the Navy Seals are clearly activating, releasing
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       more of the neuropeptide Y than the other soldiers are. So the

       highly resilient soldiers release more norepinephrine and more

       neuropeptide Y, so they can generate the stress response, but

       they can turn it off as well. We found that, in fact, that the more

       neuropeptide Y you released, the less you were likely to freeze

       under stress, or to, what we call dissociate, during these stressful


                  So what do we see in PTSD? Well, what you see on the

       top are healthy people during placebo administration, and during

       yohimbine administration, which raises the neuropeptide Y release.

       In green, you see people with PTSD, and people with PTSD on

       yohimbine. So what’s interesting is that people with PTSD release

       more norepinephrine, but they release less neuropeptide Y when

       given yohimbine, suggesting that they have a problem in recruiting

       those mechanisms in the body that turn off arousal once it


                  So the data that I’ve shown you just so far suggests that

       the adrenergic, or the noradrenaline activation is a key component

       of the adaptive response to stress. But in PTSD, we see a number

       of different ways in which people have problems turning off arousal
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       once it gets turned on. One is that the adrenergic alpha-2

       yohimbine receptors are not functioning as well, so the

       norepinephrine nerve cells can’t turn themselves off. The other

       problem is that they’re not releasing as much neuropeptide Y, so

       the arousal responses aren’t turned off via that mechanism, either.

                  Let’s talk a little bit about resilience, and what I mean by

       that. There are lots of great poems, but this is a good example. If

       you can keep your head while all about you are losing theirs and

       blaming you, if you can force your heart and nerve and sinew to

       serve your turn long after they are gone, and so hold on when

       there is nothing in you except the will … so we’re talking about how

       it is that, under stress, that people can maintain their function and

       cope with what they’re going through.

                  We’ve been interested in studying how the brain does this

       coping. We use a technique called functional magnetic resonance

       imaging, and functional magnetic resonance imaging is a

       technique for measuring blood flow changes in very localized areas

       of the brain. Let me just tell you very briefly how it works. When a

       nerve cell is activated, it activates nerve cells that are directly

       affecting the blood flow in the brain, so that although we’re
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       measuring blood flow, what we’re really looking at are changes in

       brain nerve cell activity.

                  I don’t have time to go into the studies in detail, so I’m just

       going to give you the results of the research. This is a study led by

       Rick Yun, a member of our faculty. When people are mastering

       the stress, the prefrontal cortex, the high … the control area of the

       brain suppresses the activity of the amygdala. You could call that

       an emotion center of the brain. So that they’re able to keep control

       of the emotion, basically.

                  When people are failing under a stressful situation, you

       see the reverse. The amygdala emotion center suppresses the

       activity of the prefrontal cortex. What’s interesting is that that

       situation, where the amygdala is suppressing the activity of the

       prefrontal cortex, it not only affects the function of the prefrontal

       cortex in that moment, but there’s a carry over effect where, in the

       subsequent trials, the prefrontal cortex remains dysfunctional.

                  So what we have with functional magnetic resonance

       imaging studies now, from our group, and consistent with other

       word, is the experience of failure under stress tends to produce two

       kinds of things, in the moment that you feel overwhelmed, as the
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       emotion areas of the brain cause dysfunction within the executive

       control regions. Then there’s this feeling of helplessness, even

       after that passes, which is following failure that there may be

       persisting dysfunction in the prefrontal cortex for some period of

       time. This is set up for compromised resilience, and even for

       problems like post traumatic stress disorder.

                  So now let’s talk a little bit about conditioned fear. I could

       ask you, where are the improvised explosive devices hidden in this

       alley? Now, if I told you that this was an alley in New Haven,

       Connecticut, you’d probably say, there are no improvised explosive

       devices, because nobody makes improvised explosive devices that

       I know of in New Haven. But if you were a soldier who just came

       back from Iraq, from Baghdad, or Fallujah, or from any of these

       other places, and you looked at the same alley, and you were used

       to going through streets, and knowing that your life depended on

       seeing hidden bombs and explosive devices, and you looked at

       this alley, you might become extremely uncomfortable. You would

       become extremely uncomfortable because all of these places are

       places where you might think … you might know you’re in

       Connecticut, where there are no improvised explosive devices, but
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       you might feel like there just might be something there.

                  So in PTSD, people learn to associate particular stimuli

       with threat, like a sound of a gun fire. This through(?) generalizes,

       so that other sounds that sound like gun fire are very arousing, and

       sometimes even upsetting. But also, there’s amore general

       process where contexts, crowded streets, dark places are

       associated with threat, also produce this hyperarousal, even in the

       absence of anything in particular that looks particularly dangerous

       or reminds them in any specific way of something that happened

       when they were stressed.

                  We’ve been studying this. The field has been studying

       this. This is a figure from Scott Rauch at McLean Hospital, that

       illustrates very nicely that the traumatic memories activate the

       amygdale, remember, that emotion center that I was talking about

       that was linked to mastery and failure. Well, this amygdale is very

       hyperactive when people with PTSD are exposed to reminders of

       their trauma.

                  How does this relate to the issue of resilience? We’ve

       been studying three groups, soldiers who were never in combat.

       This is led by Deane Aikins in our center. Soldiers who were in
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       combat but never developed PTSD. And soldiers who were in

       combat who did develop PTSD. We’re interested in what happens

       to the activity of this amygdala when they are learning to associate

       a particular yellow light with shock, or a white light with safety, no

       shock. So we’re interested in how they learn danger, and how they

       learn safety after they’ve been exposed to their stress.

                  So we had these two interesting findings, which is, what

       were the characteristics of the resilient soldiers? What were the

       characteristics of the group that developed post traumatic stress

       disorder? The resilient group showed the biggest change. In other

       words, they got a lot of amygdala activation when they were

       learning the danger cue. But they learned to turn off the amygdala

       when they were exposed to the safety cue. So the difference

       between danger and safety learning was very prominent in the

       resilient group.

                  In the PTSD group, they learned to activate the amygdala

       to the danger cue, but when they were exposed to the safety cue,

       they would get a little bit of turn off, but it would come back up. So

       they could get all the danger learning, but they couldn’t learn the

       safety cue. There, the amygdala was hyperactive all through the
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       safety cue relative to the other groups. So what you see is that

       among people who are resilient, there’s a capacity to turn on and

       turn off alarm responses, but in people who have post traumatic

       stress disorder, it’s hard to turn that off. They’re sort of stuck in

       threat mode.

                  In summary, what I’ve shown you is some evidence that

       the amygdala and the prefrontal cortex, their interplay is involved in

       resilience and post traumatic stress disorder ; that in resilience,

       you have flexible activation of the amygdala, that is appropriate, or

       matches the danger or the safety of the context that they’re in.

       These people are able to maintain their prefrontal cortical function,

       even in the context of amygdala activation, so that they can cope

       with stress.

                  PTSD, though, seems to be associated with an inability to

       recognize and appreciate safety. That makes their recognition of

       danger much less functional, because they see danger

       everywhere, and if you see danger everywhere, that doesn’t help

       you to focus your attention on a real threat. It’s all noise. Also, the

       amygdala hyperactivity compromises executive function, makes it

       harder to cope, and harder to beat the PTSD. So we’ve talked
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       about alarm dysregulation, failures in resilience, conditioned fear.

       I’m going to finish up now by talking about depression and


                  Following up the work of Avshalom Caspi and Terrie

       Moffitt and their colleagues, one of my colleagues in our center,

       Joan Kaufman, has been studying maltreated children, kids who

       have been removed from their home because of severe abuse and

       maltreatment in Connecticut. What she finds is a story both of

       resilience and of vulnerability. You’ll see LL, SL and SS up there.

       Those are the three versions of the genes that code for the

       serotonin transporter, which is place where Prozac acts in the

       brain. So the people who have SS have fewer Prozac receptors.

       The people who have LL have more of those receptors that take

       up serotonin.

                  What you see is that if you’re a child, and you’re not

       exposed to extreme stress, then it doesn’t really matter what

       version of the serotonin transporter gene you have. Most kids

       aren’t depressed, and these kids aren’t depressed. But if you have

       been … these are severely maltreated kids, if you are severely

       maltreated, then, two interesting stories are here. The kids that
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       have the genotype that make fewer serotonin transporters, are

       very vulnerable to depression. And depression, as you know, is,

       you would think, a common consequence of maltreatment, and

       here you see it is in this group.

                  But there’s another story. The kids that have a lot of the

       serotonin transporters, they don’t get depressed, even though

       they’ve been exposed to exactly the same kinds of maltreatment.

       So the effect of the bad environment on the behavior somewhat

       depends on what kind of genotype you have, whether you are

       intrinsically a little bit more resilient, intrinsically a little bit more


                  We’ve tried to take this story one step further, which is, to

       see whether there is a chemical fingerprint of this serotonin related

       vulnerability or a traumatic effect on serotonin. We use a

       technology called positron emission tomography, and this is a

       technology that we use to localize and quantify the receptor sites,

       in this case, for serotonin in the brain. This is the way that it works.

       If you imagine that these little hooks are the serotonin receptors,

       we give a radio tracer that binds very specifically, and we give it as

       an injection, and the tracer goes all over the brain. And we make a
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       movie, essential, over time, about where the radio tracer is in the

       brain, which we can measure with the PET scanner.

                  What you see over time is, in the areas of the brain where

       there are no receptors … all right, this should work … in the areas

       of the brain where there are no receptors, the radio tracer washes

       away very quickly. In the areas of the brain where there are lots of

       receptors, the radio tracer sticks around. So we can measure the

       density of the receptor in the brain, in this case, the serotonin 1B

       receptor. This is what we found. This is a study led by Alex


                  In two areas of the brain involved in reward, and in

       emotion, that you see the same kind of pattern. And the pattern is

       this, that in people with PTSD who are not depressed, in other

       words, who have a less severe version of PTSD, and a version that

       may not be so tightly associated with the serotonin transporter

       function, that there’s a little bit of a reduction in the density of the

       serotonin 1B receptor. But in the people who had the most severe

       PTSD, where you also see depression, they have even a more

       severe reduction in the density. So we have the genotype of the

       serotonin transporter gene, and now we are beginning to have a
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       fingerprint of how that gene plays out in terms of changes in the

       function, the chemical function of the serotonin system.

                  This is the last point that I want to make, which is that we

       think of PTSD as a problem of emotion and a problem of thought.

       But it may also, in the long term, not the short term, but in the long

       term, be a problem of brain structure. There’s elegant animal

       research from many, many laboratories. One of the pioneers in

       this area was Dr. Bruce McEwen, that suggests that when you

       expose animals to severe and chronic stress, that some of the

       connections in the brain start to retract.

                  One of our colleagues, Doug Bremner and Dennis

       Charney, did an MRI study which provided the first evidence that

       maybe, in some people with chronic post traumatic stress disorder,

       an area in the brain involved in memory called the hippocampus,

       was shrinking. There had been subsequent work to suggest that

       this isn’t the only area of the brain affected by stress, that emotion

       area called the cingulate gyrus that I was just showing you up there

       is also affected. But that in PTSD, over long periods of time, that

       there may be possibly reductions in the volume of certain parts of

       the brain. That’s the bad news.
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                  The good news is that there are some data to suggest,

       both in animal research studies, and now in clinical research

       studies, that long term treatment with the medications that we’re

       using to treat post traumatic stress disorder, in other words, first

       shown with the antidepressant medications, may ameliorate some

       of these structural changes. The point is that structure and

       function in the brain are closely related, and more so than we ever

       thought before. As we’re studying PTSD, we’re taking the

       research to these more basic levels.

                  Let me now conclude. What have we learned? We’ve

       learned that alarm is necessary for resilience. Resilient people

       have a capacity to mobilize the stress systems in the body. But, to

       dampen the impact of alarm, so that there’s not a long term

       negative effect of being stressed, you get stressed, you get better,

       you get stressed again. You get better again. And it’s also, fear

       conditioning is necessary. Resilient people have a capacity to

       match arousal to the changing context. They don’t get stuck in

       danger mode. And they’re not Pollyannas. They see the danger

       that’s there.

                  Depression, as in this kind of depression, in part, is an
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       expression of a resilience failure. Resilient people preserve

       executive cognitive function under conditions of high emotional

       demand. They do not become immobilized or helpless. Acute

       stress becomes PTSD in the context of failure in multiple systems,

       alarm conditioning, and we’re just now beginning to get insights

       into the molecular mechanisms that underlie this thing. Let me

       finish by acknowledging the support of the Department of Veterans

       Affairs, NARSAD and other groups for the research, the work of

       our colleagues, Deane Aikins, Doug Bremner, Dennis Charney,

       Andy Morgan, Alex Neumeister, Joel Gelernter, who did the

       genetics, Steve Southwick, and our collaborators at the US Military

       Academy, and the Special Forces Training Program. And thank

       you for coming today.


                  JEFFREY A. LIEBERMAN, M.D.: John, thanks for a

       fantastic presentation. We’re going to take questions now. If you

       could please come to one of the microphones, try and keep your

       question as succinct as possible, and we’ll take ten minutes of

       questions. Yes, sir.

                  MAN: (Inaudible Portion) Special Forces Training people,
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       and I came across a manual a number of years ago that included a

       lot of work on using breathing exercise training. And also, up at

       Yale, years ago, there was a man who actually was curing, was

       treating emphysema patients, Carl Stowe(?) using breathing

       exercise. He was a singer. So my question is, given how

       remarkable the resilience is of Special Forces training, has

       anything been done looking into that mode of increasing resilience

       in people with PTSD using the whole … really great potential area

       of breathing exercise, as it has all kinds of infinite possibilities.

                  JOHN H. KRYSTAL, M.D.: Right. So I think that’s an

       excellent point, and so some of the things that we’ve been learning

       about how people cope with stress have to do with how people

       learn to get the signals from their body when they’re tense, and

       learn how to relax. Deep breathing exercises are a very important

       part of that. So people are using yoga, and mindfulness therapies,

       and a variety of relaxation approaches that help people to learn,

       people who have problems learning how, turning off the alarm

       response, they can learn, and through some of these approaches,

       how to turn off that response, and deep breathing is part of the tool

       kit that they use already, and that’s very important for a lot of
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                  JEFFREY A. LIEBERMAN, M.D.: Mr. Schusterman(?).

                  MR. SCHUSTERMAN: Hi. Is there any relationship

       between phobias and PTSD?

                  JOHN H. KRYSTAL, M.D.: Sure. A simple phobia like

       snake phobia or insect phobia …

                  MR. SCHUSTERMAN: (Inaudible Portion)

                  JOHN H. KRYSTAL, M.D.: … are often developed

       because people are frightened when they see something, and

       have just that conditioning part. It’s a more limited part of the fear

       learning. Absolutely. And some of the techniques for treatment that

       we use in PTSD first get worked out in phobia, which is a little

       simpler and a little less complicated, and we bring that into the

       PTSD. So there are a lot of connections in terms of phobia and

       PTSD as fear learning. Absolutely.

                  MR. SCHUSTERMAN: Just one other thing. Why six

       months for SSRIs to become effective?

                  JOHN H. KRYSTAL, M.D.: It’s not six months before they

       become effective, but the changes in the brain are extremely

       gradual, so it’s only six months before you see the changes in
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       brain structure. The changes in brain structure occur on a time

       course that is much more slow than the changes in symptoms.

       Symptoms change probably between six and 12 weeks usually

       with SSRIs. But the brain structural changes take a long time to be


                  MR. SCHUSTERMAN: Thank you.

                  JEFFREY A. LIEBERMAN, M.D.: Yes, Ma’am.

                  WOMAN: I just wanted to ask. I saw an interesting

       program on a new type of treatment for PTSD. It was television,

       and it involved the person actually reliving the event over and over

       again with a really trained therapist, and apparently this is very

       successful over a long period of time.

                  JOHN H. KRYSTAL, M.D.: Right.

                  WOMAN: And it doesn’t involve medication. It’s just sort

       of a retraining the brain.

                  JOHN H. KRYSTAL, M.D.: Yes.

                  WOMAN: How would you relate that to your research?

                  JOHN H. KRYSTAL, M.D.: Sure. So generally, there are

       two … something called progressive exposure, where you

       gradually expose the person to more and more of the experience
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       of the trauma, is one of the very common and very well established

       types of treatment for post traumatic stress disorder. It does two

       general things that relate to what I’m talking about today. The first

       is, when you activate a traumatic memory, that memory and the

       reactions associated become, you might say, more plastic. You

       have an opportunity to do what we call extinguish the maladaptive

       part of that memory, or to affect that. So extinction of fear through

       exposure is a very well established part of that, and we’re

       beginning to understand the biology of that extinction better than

       we ever did before.

                  Plus, when people begin to extinguish, or reduce how

       strongly they react to the memory, they also have a stronger

       feeling of mastery. That feeling of mastery is also adaptive. It has

       the opposite effects of failure. Mastery has positive changes in the

       brain. Failure has negative change in the brain. It’s not that they’re

       neutral. They are the opposite of each other. So I think both of

       those kinds of reactions can occur in the context of those


                  JEFFREY A. LIEBERMAN, M.D.: Yes, sir.

                  MAN: Doctor, do you ever see a time when the armed
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       forces will use the results of this research as a prescreening

       technique for combat soldiers?

                  JOHN H. KRYSTAL, M.D.: I don’t know if it will be used

       as a screening. I don’t know if the American army will use it for a

       screening process. I know that the Israeli army, where I’ve had a

       number of interactions with, uses a variety of very intensive

       screening battery to help to direct people to one part of service or

       another. American army, I don’t think, quite so specifically and

       directly does that. They do a fair amount of screening. I’m actually

       a member of the Department of the Defense Mental Health

       Advisory Group which looks at what they’re trying to do, and

       develops their programs.

                  I think one of the really hopeful areas that some of this

       research might go is to introduce forms of resilience training, so

       that people, and when they come in the military, that some

       assessment is made of their intrinsic capacity for resilience. And

       then they help people to develop the skills that generally make

       people more resilient. I’m not alone in thinking that we can help

       people to develop and learn skills. After all, a lot of these kids are

       18, 19, 20, 21 years old, coming right out of high school and going
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       into the army. They have a lot to learn. And the army tries to do

       some of that, and I think they’re going to do more of that.

                  (PART TWO)

                  MAN: Thank you.

                  JEFFREY A. LIEBERMAN, M.D.: Yes, Ma’am.

                  WOMAN: I’m from Pittsburgh, and I’ve had the privilege

       of working with Kathy Wisner, with Western Psychiatric Institute

       and Clinic. We have a community advocacy, nonprofit, and we’re

       now looking at college students, and trying to look at preventive

       measures to teach them resilience. I want to know your opinion of

       it, and we’re thinking of application in the wellness centers. We’re

       bringing together the centers for counseling because the

       universities are overwhelming with really sick kids now, and we can

       help kids deal with the transitions of coming into college. What is

       your opinion of the adaptability and teaching prevention through


                  JOHN H. KRYSTAL, M.D.: well, prevention is always

       better than cure. Right? So I think the idea of preventive,

       resilience enhancing interventions is a relatively new idea. There

       are a couple of groups like the University of Pennsylvania that
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       develop these positive psychology training programs. Ironically,

       one of the guys who is involved in that, Marty Seligman, was one

       of the people who helped to identify learned helplessness way

       back in the sixties. But we know a lot less about it. I’m hopeful

       that these sorts of processes in general, helping people to look at

       themselves, and to take care of themselves, and not let

       themselves sort of become overwhelmed, so completely

       overwhelmed, could have a very positive effect. So it sounds like a

       great program.

                  WOMAN: Thank you.

                  JEFFREY A. LIEBERMAN, M.D.: Yes, Ma’am.

                  STACY: Hi, my name is Stacy(?). You were talking in

       the beginning of your presentation about the relationship between

       the cerebral cortex and the amygdala. I was wondering if there

       are, at this point, any medications or treatments that can be used

       to kind of slow down, suppress, or stop the amygdala in a case

       where someone with post traumatic stress disorder is engaged,


                  JOHN H. KRYSTAL, M.D.: Right. I wish I could say that I

       knew the answer to that question. There’s animal data that
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       suggests that some of the treatments that we are using may affect

       that interplay, some of the antidepressant, some of the

       benzodiazepines. I think that this kind of thinking is a path that will

       help to bring us to new and more specific treatments as well. I

       would that an effect for treatment for PTSD would have to do just

       what you’re saying.

                  STACY: Thank you.

                  JEFFREY A. LIEBERMAN, M.D.: Yes, Ma’am.

                  WOMAN: I’d just like to know your opinion about the use

       of EMDR with post traumatic stress disorder.

                  JOHN H. KRYSTAL, M.D.: Sure. There is empirical data

       now that suggests that EMDR is as effective as the other types of

       exposure treatments for post traumatic stress disorder. I don’t see

       any evidence that it is uniquely effective, but it is as effective. I

       also don’t see any evidence that the … EMDR includes an eye

       movement. That’s what the E and the M are. There’s no evidence

       that the eye movement part has any connection to the

       effectiveness of the treatment. Interestingly, the bottom line is that

       EMDR is one of those treatments that exposes people to their

       traumatic memories in a way that they can tolerate, that’s not
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       overwhelming, and helps them to extinguish the fear responses

       over time, and gain a sense of mastery. So it is an example of one

       of the treatments that works in that way.

                  WOMAN: Thank you.

                  JEFFREY A. LIEBERMAN, M.D.: Yes, Ma’am.

                  WOMAN: Thank you. My question is really just a time

       frame question. I’m talking about your example with the Navy

       Seals and the stress they were under. It seems like a very short

       period of time later that you’re looking for the symptoms being

       ameliorated …

                  JOHN H. KRYSTAL, M.D.: That’s right.

                  WOMAN: … of the fight-or-flight. Then how do you

       compare that to post traumatic stress disorder where the fight-or-

       flight has been going on for nine months? Are there periods of

       amelioration along that, or … can you elaborate on the time frame?

                  JOHN H. KRYSTAL, M.D.: Sure. You raise a very

       important limitation of the Navy Seal research. Ideally, we would

       follow these guys after their intensive training program, out for a

       very long period of time to see if that initial response predicts

       whether they’re vulnerable to developing PTSD. We don’t know
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       the answer to that. There are some other data that would suggest

       that there is some ability to predict later response from the early

       stress responses, but we need this kind of research that follows

       people all the way through, and there are a couple of groups in the

       country now, doing this in the Marines and some other groups of

       soldiers that may help to answer the very question you’re asking.

                  WOMAN: So what is the usual amount of time you see

       between the fight-or-flight response and …

                  JOHN H. KRYSTAL, M.D.: PTSD?

                  WOMAN: … it going away?

                  JOHN H. KRYSTAL, M.D.: So, people are complicated,

       and … (Laughter) so the research has looked at the patterns of

       stress response that people have. There are some people who

       are very extremely distressed right after their traumatic event. This

       is research published from the group at Walter Reed. A certain

       percentage of those people who seemed to be in very bad distress

       right away will get better and not develop PTSD. But there are

       some people who don’t have PTSD at all, after the bad event, who

       will, over the next months or even years, develop post traumatic

       stress disorder. And we don’t understand that. We really don’t
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       understand that, and it’s a real mystery for us.

                  WOMAN: Thank you.

                  JEFFREY A. LIEBERMAN, M.D.: I hate to do this, but

       we’re going to have to call a halt to questions to this presentation,

       so our schedule doesn’t get out of control. So let’s thank Dr.



                  JEFFREY A. LIEBERMAN, M.D.: One of the unmet

       medical needs that’s been recognized in recent years is in

       women’s health. Nowhere was that more particularly the case than

       in women’s mental health. And it’s been through the efforts of

       people like our next speaker that women’s mental health has

       become a major area of emphasis in research, in psychiatry and in

       the field of mental illness research. Dr. Kathy Wisner is a

       Professor of Psychiatry, Obstetrics and Gynecology and

       Reproductive Sciences and Epidemiology in Women’s Studies at

       the University of Pittsburgh School of Medicine, and will speak to

       us about depression in women across the life cycle. Please

       welcome Dr. Kathy Wisner.

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                  KATHERINE WISNER, M.D.: Well, thank you for that

       introduction, Jeff. I would also echo my admiration for NARSAD.

       My own experience with NARSAD is, at the time when I was

       beginning my work to consider how reproductive hormones might

       be related to mood effects in women was a time when we in

       America were arguing whether there really was such a thing as

       post partum depression. At that time, NARSAD saw fit to fund

       some of my early work, so I’m every indebted and thankful.

                  I’d like to start with a look at the prevalence of depression

       in women compared to men across the life cycle. So what you see

       is the prevalence rate of depression across various age categories.

       This graph, this line, is the prevalence in women, this is in men.

       What’s striking is what I call this epidemiologic injustice, that in fact,

       right at the time when are having children, right at the time they’re

       expecting to be marrying, having families, is a time of very high

       prevalence for depression.

                  Additionally, this time frame, which is the five years before

       a women stops having periods, so the five years before she

       becomes menopausal is another very high risk time. Another

       interesting piece of this is that if you look at children, it’s right about
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       the time of menarche that this curve begins to separate. Now, you

       also know that until about 1993 or so, there was no requirement to

       include women in NIH funded research projects. It was at that time

       that the enactment of legislation that women needed to be included

       in federally funded studies was developed. So until that time, there

       was really a sense that the model for health research was the

       male, and that women were sort of small men, which we now

       know, after a lot of research, is not the case.

                  The other point is that the justification for excluding

       women from earlier studies is that women are really messy. Right?

       I mean, if you’re trying to look at a treatment, no matter what it is,

       and you’re following a woman across time, she has these things

       called menstrual cycles, and pregnancies, and postpartum

       (Inaudible), and it’s very difficult to separate out what the impact of

       the treatment is if there’s all this other stuff going on.

                  Well, I’m happy to say that this has really reversed over

       the last decade, so that now we’re seeing these changes that

       occur in women’s physiologies as actual benefits. So I coin this

       term, the longitudinal laboratory of women’s lives; because if you

       think about challenging someone, particularly with a hormonal
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       challenge, the magnitude that you get during pregnancy, there is

       no human subjects IRB, no ethics board, that will ever approve that

       as an experimental intervention, but you can certainly do that

       because it happens naturally. So from messy, we’re now being

       viewed as great ways to study the impact of hormones on mood

       and other aspects of women’s physiology. So, a major change in

       the way women are viewed just over the last couple of decades.

                  Much of my work is focused on women who become

       pregnant, and how one manages major mood disorders and other

       psychiatric illness during pregnancy. You’ll notice that I use the

       term gestational depression. That’s not a coincidence. I’m trying to

       make the point that, just like gestational diabetes, gestational

       hypertension, that this is a major medical illness that occurs during

       pregnancy, and deserves research.

                  When I do a talk like this, I’m also worried about speaking

       about mental illness as if it’s in the abstract. It is such a powerful

       force in the lives of women that I see, that I wanted to put up this

       poem, which really describe what it feels like for a pregnant woman

       who’s severely depressed. This is a patient of mine who was a

       psychiatric nurse. I’m always struck, no matter how many times I
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       read this, by the last stanza, which is, you say I’m carry life inside.

       How can that really be? How could life possibly survive in a

       nonexistent me? She also brings home the point to us that she is

       literally the container, the life giver for this organism growing within

       her, and again, to have to fight with major mental illness during

       pregnancy is, again, I think, an epidemiologic injustice.

                  Depression during pregnancy or at any time in a woman’s

       life is not a good thing. That’s not news to this audience. In

       addition to the physiological effects of depression, where you have

       changes in appetite, in activity levels, difficulty with sleep, all of

       these body rhythms that occur across 24 hours are disrupted in

       depression, so you have that. You have the cognitive difficulties,

       the taking care of self, organizing yourself to get to your

       obstetrician, organizing your dietary intake. A woman’s exposure

       to depression is not only the physical, the physiological

       dysregulation, but also the whole way in which it then sets her up

       to relate to her world and to access those things she needs to have

       an optimally health pregnancy.

                  Women in our studies who become pregnant, who are

       depressed, also have higher body mass index, high weight than
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       women who are not depressed, or women who are treated. They

       use more drugs and alcohol. What worries me as well is that the

       quality of the interpersonal relationships become compromised. It’s

       so important to be able to access other people during pregnancy

       and postpartum, so most women will have this sort of shopping

       mall phenomenon where they go to a shopping mall and they say,

       oh, look it. There’s so many women who are pregnant.

                  Well, when they’re not pregnant, they don’t notice them.

       But there’s this affiliation to connect with other couples having that

       same experience, and to group with those folks after birth. So you

       can figure out, how much does your baby spit up? Is this normal?

       Those interpersonal connectedness aspects are incredibly

       important to the mother, and her family in terms of development,

       and a lot of my patients are cut off from the ability to do that due to

       social withdrawal. Depression also affects reproductive outcomes,

       most particularly birth weight and preterm birth risk. So this is not

       a good thing in pregnancy.

                  So many women develop early onset anxiety disorders

       and then depressive disorders, and are treated for depression

       medically by the time they enter pregnancy. So one of the areas of
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       research that I’m doing is to try to improve the treatment of

       depression during pregnancy. No one would elect medication if

       they didn’t need it; but again, many of these women are stable on

       medication therapy, and once that choice is made, we need to

       make sure that we’re treating women well during pregnancy.

                  One of our problems is that we know that if you continue

       medication during pregnancy, about 68 percent of women will

       remain well, so that there is some recurrence risk, even if you

       continue medication. What the problem here is that if you continue

       medication, and I got this flipped around though, if you continue

       medication, the recurrence risk if 26 percent. So think about what

       that says, though. If a woman’s going into pregnancy and you tell

       her, even on your medication, your risk of recurrence is about one

       out of four, if you discontinue your medication it’s about two out of

       three, that difference is significant. But the issue for me here is,

       why is a woman who’s stable on medication, who goes into

       pregnancy, why does she have a one out of four risk of becoming

       ill? The women will say, gee, so does that mean I’ll be exposed

       and not have a protective effect?

                  One of the reasons that we believe is contributing is that
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       the physiology during pregnancy changes dramatically, so that

       when a woman takes a medicine in pregnancy in the first trimester,

       it’s very different than in the third trimester; because you know this:

       women are hot in the third trimester. Their pulse rates are higher.

       They’re really metabolizing for two. They have their metabolic

       load, and the metabolic load of the fetus as well; so they’re

       metabolizing for two, and that includes any medication she takes.

                  What we found in the early nineties was that women who

       were maintained on an antidepressant actually needed to have

       their dose increased across pregnancy to stay well. Tat’s what this

       graphic is showing, that across pregnancy, women who were

       stable on this dose had to go up in the latter part of pregnancy.

       About a decade later it was shown that the enzymes that

       metabolize these drugs, tricyclics, are actually induced in the final

       trimester, so we were seeing a phenomenon that since then

       validated, but we reported at that time that the doses need to be

       increased in the latter part of pregnancy, because taking your

       usual dose of antidepressant leads to a serum level about half of

       what it would be prior to or in the early part of pregnancy. So one

       issue is, we don’t know very well how to dose women. There aren’t
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       good pharmacokinetic studies during pregnancy. So once again,

       that decision to treat has been made, I think we owe it to women to

       treat them in the most optimal way we can.

                                  Since then, our group has done a couple of

       other studies. This is Zoloft. This is a little bit of a different curve.

       This is the average serum level in women at 20 weeks pregnancy

       compared to 20, compared to 36, delivery, and this is postpartum.

       And you see the same phenomenon. So the level, corrected for

       dose, is decreasing across pregnancy to delivery. So that if the

       women’s needs, say, this amount in her blood to stay well, you can

       see what will happen. She’s going to recur there without a dose


                  This is counterintuitive, because most physicians will say,

       gee, she’s pregnant. I’m going to try to use the very lowest dose.

       But in fact, then, what will happen is, she’s very likely to become

       depressed, and she will have two exposures. So this is citalopram,

       or Celexa. The different curves are metabolites, but you can see

       the curves are basically the same. Across pregnancy, the levels

       go down, and then there’s a rebound effect postpartum. We found

       this particular graphic type for all of the SSRIs. Again, this is not
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       something that’s widely known.

                  What I’m also trying to do is expand our tools, because

       again, I really want to find treatments that can be given to pregnant

       women that don’t involve drug exposure. So one candidate is

       bright light therapy, which I’m sure people are very aware that, for

       those of us that live up in the north, the sunshine is very rare

       during these winter months, and in fact, bright light treatment has

       been developed now over two decades ago for winter onset, or

       seasonal depression. What is less well appreciated is that bright

       light therapy is effective also for nonseasonal depression. So we

       then began to look at bright light treatment, delivered in the

       morning, and I’ll show you a picture next, for women who were

       pregnant and depressed; because if there’s a somatic, physical,

       nondrug treatment for such women, we certainly want to explore


                  This is how a woman would, say, one of our pregnant

       patients, might sit. She sits in front of the light for a half hour to an

       hour. She doesn’t have to look at the light, but she needs to be

       about 12 inches from it, so her eyes are exposed to the light, but

       she can read. Our moms do baby books, knit, pay bills, write
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       books. They’re a very creative group. So as soon as she gets up

       in the morning, at a specific time for her, she would then sit in front

       of this box and get this bolus of very bright light, that’s as bright as

       being outside on a day like today at around noon.

                  The first study that we did is graphed here, where we

       have the women who had no light … we’re following them for two

       weeks … this is the common Hamilton Depression Rating Scale

       that we use to look at severity. Then we introduce the light here.

       So you can see this decrease from mid twenties, which is very

       substantial depression, down to under ten, which is very similar

       across five weeks to what you might see from a drug effect.

                  Now, we’ve done a small randomized trial, and a

       colleague of mine has done a larger randomized trial of the light

       treatment versus a control treatment, which shows an effect size

       that is very similar, or even a bit better than antidepressant

       medication. So we’re about to launch a large scale study to look at

       bright light therapy for treatment of depression during pregnancy.

                  Hot in the news these days is postpartum depression.

       About one out of seven women have depression at some point in

       the nine months of pregnancy. One out of seven women have
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       depression in the first three months postpartum. So there’s a

       concentrated period of time for the development of depression.

       We undertook a screening program in Pittsburgh, because if you

       think about this, if you’ve got one out of seven women becoming

       depressed postpartum, why isn’t there some sort of national

       screening program for this? We screen for phenylketonuria, which

       is one in what … 10,000 or so babies. That’s a required screening.

       Here’s something that’s one out of seven.

                  Well, New Jersey and Illinois have passed laws, so that

       screening is required in those two states. In fact, in the Healthcare

       Reform Act, the infamous December 24th legislation, there are

       components that would mandate research and education about

       depression. There is a component by Barbara Mikulski to require

       screening at a national level. So we’re making some progress.

                  What’s the scientific case for screening? Certainly it’s

       very common. Certainly it’s not a good thing. If affects

       reproductive outcomes. It affects the quality of the mother-infant

       relationship. In severe cases, it affects the growth and

       development of the infant. So it’s certainly an important problem.

       We have very easy screening measures, very simple to use
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       measures, and the most common of those is called the Edinburgh

       Postnatal Depression Screening Scale. Quick, ten item report.

       You can fill it out in an obstetrician’s office, add up the score, very

       easy. Available in 23 languages. It’s scored from zero, basically

       meaning no symptoms, to three, which is the highest level of

       symptoms. So it is a score from zero to 30. Ten or more is typically

       the lowest cutoff that’s recommended if you have the resources to

       evaluate the patients. Thirteen or more is recommended for most

       clinical setting. So there are different cut points.

                  Let me show you what we’re doing now. We have a

       hospital in Pittsburgh, Magee-Womens Hospital, in which deliver

       just under 10,000 babies per year. Our objective is to visit every

       one of those women who deliver there and talk about postpartum

       depression, give them a pamphlet, and offer them a chance to be

       screened at four to six weeks after birth, by phone, by our research

       team. So we collect these consents. They’re actually waivers of

       consent from the women at our hospital. At exactly four weeks,

       our staff starts calling them morning, afternoon, evening, weekend,

       and we have a list of alternative contacts that we call as well, really

       trying to screen these women for postpartum depression.
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                  When we get them on the phone and screen them, if they

       have that score of ten or more, we offer them a home visit. Or,

       sometimes women, particularly women in domestic violence

       situations, will want to meet at the shopping mall or the local fast

       food store, wherever they want to meet. So we do a home visit, do

       an educational evaluation, a full diagnostic work up, and talk to

       them about resources that would be available for treatment.

                  In that particular study, we also have a randomized part

       where they can be randomized to an intervention called

       Depression Care Management, which is basically phone coaching.

       One of my staff will keep in touch with them, try to reduce barriers

       to getting into care, versus a treatment as usual, which is just the

       education. So that part of the study is still ongoing, but I can show

       you some of the screening results.

                  This is this measure from zero, meaning no symptoms at

       all, up to 30, which is really ill. You can see that across about

       6,000 of these tests that were given, our average is somewhere in

       here. If you get to the cut offs, ten or more, or 13 or more, you’re

       really looking at a little over ten percent of the population at ten or

       more, and probably around six percent of the population at 13 or
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       more, which fits with what we know about the epidemiology.

                  In this sample, then, this is from some months ago, but

       the data, or if we have about 11 and a half thousand women

       agreeing to be called out of the number we approach, that actually

       is surprising to our NIMH project officers who thought women

       wouldn’t be willing to be screened. But they really are willing to be

       screened, and a lot of the women who don’t want to be called say

       I’m already in treatment, or my doctor put me on preventive

       medication. So I think we are making progress.

                  We’ve reached about 74 percent of those patients. When

       we reach them, we screen them. But look at this, 14.1 percent of

       the women in Pittsburgh, very similar to the 14.5 estimate

       nationally, again, one out of seven women, screen positive for

       depression. So it is not a rare thing.

                  What kinds of diagnoses do our women who screen

       positive have? This is a depression screen, so we think that we’re

       screening for depression, and in fact, we know that’s the most

       common type of disorder, depression. But we made a careful

       distinction between unipolar and bipolar depression.

                  There is good evidence that bipolar disorder has its onset
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       for the first time in a woman’s life in the post birth period, or is

       exacerbated, or she may have depression and then has her first

       hypomanic or manic episode post birth. We found one out of five

       women in the positive sample had bipolar illness, and it was almost

       always not diagnosed. So one of the concerns we have now is,

       given that the screening for depression takes place often in

       obstetrical or primary care settings, what kind of tool can we give

       our colleagues to identify these patients who screen positive for

       depression who actually have bipolar disorder?

                  We also found primary anxiety disorder, and again, these

       are a list of primary disorders. This is interesting in that only four

       percent of our sample with this relatively low cutoff of ten or more

       had no diagnosis or a diagnosis such as adjustment disorder.

       That’s a little worrisome to me, because now I wish I would have

       looked at the people who scored nine or more, because I don’t

       know what’s happening with the women who scored nine or less.

                  In terms of onset timing, when I designed this study, I put

       in this four to six weeks postpartum time frame. Well, that’s

       prevalent. So in other words, we pick up all the women that have

       depression in that time frame. When went back and asked them,
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       when did the episode begin, about 27 percent said it began in

       pregnancy, so even before the postpartum period; 36 percent said

       it began even prior to that pregnancy itself. About 37 percent said

       it began postpartum. So if I were to do this study again, and in the

       next study I’m planning … I’m doing a screen during pregnancy,

       because we certainly have a lot of women who have illness during

       pregnancy and prior to pregnancy who we pick up postpartum.

                  So when to screen, in my recommendation, is during

       pregnancy and postpartum, and in fact, the current president of the

       American College of Obstetrics and Gynecology has taken

       perinatal depression on as his initiative. So we’ve been working

       together to think about how to implement screening programs.

                  How to identify the women with bipolar disorder is another

       issue that I mentioned. There’s another point about, we are looking

       at diagnoses, and screening for diagnoses. But there’s another

       very relevant point about maternal function that we’re really not

       tapping into. So we’ve developed now a measure from the ground

       up, so, from women in the postpartum period, their sense of what

       is optimal maternal functioning? What are the components?

                  There are seven components that they identified across
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       focus group that we’ve developed into a maternal functioning

       measure that we’re evaluating because the pediatricians keep

       asking us for something about maternal function in screening;

       because they’re much more comfortable with that concept than

       screening for depression. So, again, a lot of different kinds of

       conceptual advances.

                  We need a comprehensive program model to screen for

       postpartum depression. Right now, what happens is, we can detect

       it. We can diagnose it. When we get to the step that I described,

       like with my program where we’re trying to use coaches to

       encourage women to get into the treatment of their choice, that’s

       really where this schema fails. We really don’t do very well with

       engagement treatment, because what we really want are good

       treatments that are accessible and acceptable, because we want

       our moms to have this. So we’re interactively working on this

       sequence to improve care for women.

                  Can I talk about one other little thing, Jeffrey? You going

       to come up and throw me …? Okay, so the last thing I want to talk

       about is a novel treatment, estradiol, so estradiol is a hormone. It is

       a naturally occurring hormone in the body. It’s one of the
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       estrogens. My intent here is to try to get a treatment, and if this

       treatment is effective for postpartum depression, it is a lot more

       comfortable for obstetricians to use. Or often the primary care

       providers, and many are not comfortable using antidepressants, so

       I’m trying to increase this tool box for treatment.

                  In this postpartum period, and this is some of the work

       that was funded by NARSAD earlier in my career, many of us had

       this sense that there has to be something about this massive

       hormonal withdrawal that occurs at birth that’s related to the onset

       of depression postpartum. So this is the weeks across pregnancy,

       and these are the estrogen levels, and the progestin levels. And

       you can see there’s this huge burst, a huge increase in hormones,

       and those hormones go everywhere, not just the uterus. They have

       receptors in the brain as well.

                  At birth, they come plummeting down to very, very low

       levels. So a number of spent a lot of time looking at hormones in

       the blood, the serum levels, to see, oh, gee, I’m going to find some

       deficiency, or some relationship to mood. It’s not there, because

       it’s not the absolute level in the blood. It is, in fact, this rapid

       change in hormone levels in a group of women who appear to be
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       neurobiologically more vulnerable, more responsive to changes in

       hormone levels.

                  In 1996, a forgotten study was done in England, and the

       investigator basically looked at estradiol treatment for postpartum

       depression. It was a study in which the population included women

       on medication that wasn’t effective, and women on no meds, so it

       wasn’t scientifically as vigorous as it might be. But what he

       reported was, within the first month, the women who were on

       estradiol had a rapid improvement in symptoms, and did quite well

       at maintaining symptoms out to eight months. And this is placebo

       patch group. This study was never replicated. So here we have a

       potential tool, never replicated.

                  So we were fortunate to get a grant from NIMH to

       replicate this study, sort of, to look at an estradiol patch for

       postpartum women, compare it to standard drug, Zoloft, which

       you’ve been studying for many years, versus a placebo, and follow

       the women in an acute eight week treatment phase, and

       continuation phase across time. That study is not in process,

       because again, we’d like to expand this toolbox of treatments. The

       women find it very appealing to think about estradiol being a
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       possible intervention for depression.

                  Just to close out, we actually gained our dosing for the

       postpartum study by looking at studies that were being done for

       estradiol treatment in the perimenopause, because again, this

       vulnerable, rapidly changing hormonal time frame in the

       perimenopause, before the cessation of menses, is a time when

       estradiol treatments, 50 to 100 microgram per day, transdermal

       delivery system, does appear to be effective, and with quite a good

       response rate. So we’re looking at 80, 70 percent response

       compared to 20 for placebo.

                  The study that I told you about for postpartum depression,

       estradiol, Zoloft, placebo, has never been done in perimenopausal

       depression. So again, that similar kind of comparative study,

       efficacy study, needs to be done in the perimenopause as well. I

       think I’m going to just go to this slide, which is something that is not

       in question at all, that we know for sure, and that is that mental

       health is fundamental to health. So thank you very much.


                  JEFFREY A. LIEBERMAN, M.D.: Kathy, thanks for a

       fabulous presentation. I think we’re going to want to come back
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       next year, to be able to tell us the results of that last study, which is

       a very important study, and really long overdue. We have time for

       some questions. We’ll limit it, though, to ten minutes max. Yes,


                  WOMAN: Yes, thank you. What about mothers who

       have children, and maybe they’re going to have another child, and

       it’s a time in their life that they are thinking of improving their

       career, changing their life, maybe a 35 year old woman who … she

       has a contact(?), and she wants to have a child. She has other

       children. But she’s also having problems in her marriage. So

       there are other things happening in this woman’s life that are

       affecting her, while she’s pregnant, and then, maybe she doesn’t

       get pregnant then, but after her child is five years old, she gets a

       pregnancy. And the doctor says, it’s because you waited until your

       child was old enough to go to school, and then you were a strong

       mother. You had strong instincts(?), and you then, your body broke

       down and you had your depression. So maybe a 40 year old

       woman, what are the chances of …

                  JEFFREY A. LIEBERMAN, M.D.: Let’s try and answer

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                  KATHERINE WISNER, M.D.: Is your question, then, how

       do you really integrate all of the factors that occur …

                  WOMAN: Yes, yes.

                  KATHERINE WISNER, M.D.: This is, I think, a very good

       point, because in this program, I really focused on development of

       treatments, a subset of them. We have a number of other

       treatments that we’re developing to address exactly this, because

       women are in all of these contexts, so they’re in marriages, in

       families, in communities, in society, and when we treat postpartum

       depression, we’re really trying to impact all of those relationships,

       so that the mother-infant, the marital, other relationships, are

       impacted in a positive way.

                  One of the tools that, if I come back next year I can talk

       about, is we’re looking at different ways to focus therapies like CBT

       or interpersonal therapy, or dialectical therapy to help that woman

       create relationships in the space around her in a way that’s more in

       tune with what she wants to achieve. So how does she negotiate

       having a child with her husband? How does she negotiate who

       changes the diapers? How does she work with in-laws? So those

       contextual pieces, I think, are incredibly important for her decision
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       making about when she bears children. So I think you’re right.

                  WOMAN: Let me have one more question.

                  JEFFREY A. LIEBERMAN, M.D.: No, we have to move

       on, Ma’am. Thank you.

                  WOMAN: Oh. (Inaudible Portion)

                  JEFFREY A. LIEBERMAN, M.D.: Yes, Ma’am.

                  WOMAN: Yes, I’d like to know if the use of SSRIs has an

       effect on the fetus or on the baby if the mother is nursing.

                  KATHERINE WISNER, M.D.: Could I have the slides

       back on? I sort of anticipated that question. I have a slide

       response to that. So the question is, what about SSRIs during

       pregnancy? While they’re putting the slides up, I’ll just say that

       when I talk to women about various treatments, I present the whole

       group of treatments that would be available to her. Women make

       often very thoughtful, careful decisions in weighing …

                  JEFFREY A. LIEBERMAN, M.D.: Okay. Which one is it?

                  (Background Conversation)

                  KATHERINE WISNER, M.D.: So women make very

       thoughtful decisions, and one of the things I object is when

       someone calls us and says, oh, Dr. Wisner, what’s a safe
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       medication in a pregnancy? I say that safe is not a word I use. It’s

       always a risk-benefit decision, and the woman’s sense of what is

       the most appropriate treatment for her values? So someone,

       they’ll say there’s no way I’m taking a medicine. Some women will

       say, every time I stop this medication, I’m suicidal. I lose my job. I

       have no insurance. So it’s this complicated risk-benefit decision.

       Fortunately, the SSRIs have become model drugs to study how do

       we set up studies, thinking about methodologies to get this kind of

       information? So I put this together for take home points.

                  As far as birth defects related to SSRIs, now there are

       very large case controlled studies, two from America, that show

       that taking an SSRI, overall, SSRI exposure is not related to birth

       defects. That has not been a concern for me. Well, a concern …

       has not been something I’ve studied for a while. I’m more

       concerned about other kinds of effects that never get studied for

       any drug. Think about all the drugs. Two thirds of American

       women take at least one prescription drug in pregnancy.

                  Physical malformations is not an issue for SSRIs. Growth

       effects were reported to be an issue, that is, lower maternal weight

       gain, lower birth weight, other kinds of problems. The problem that
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       is most salient, I think, is the issue of preterm birth. So we did a

       study that we published earlier this year, and that we showed over

       20 percent of women who took SSRIs had preterm births. That

       has to be tempered by the fact that we also studied women who

       were depressed throughout pregnancy and never got an SSRI,

       who had the exact same rate of preterm birth. So we’re now trying

       to figure out, is that something about the physiology of depression

       that affects both treated or untreated? Or is it something about

       SSRIs? So that’s, I think, a major research area.

                  The other issue is, what about long term effects? Well,

       depression itself has very negative effects if it’s long term also, so

       you have to balance, again, what’s a mother-infant interaction like

       with a depressed mom? Our group and others have shown some

       data that in the middle of infancy, there appears to be a subtle

       effect on motor, muscle function in infants and toddlers that

       appears to disappear by about 18 months. So there are some mild

       motor effects that disappear.

                  What I think we need are the longer term studies. What

       about kids exposed? How do they do in adolescence? Again, I’m

       talking about SSRIs, and in some ways, you shoot yourself in the
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       foot, because these are drugs about which we know more than any

       other class of drugs in pregnancy, except anticonvulsants. So it’s

       a complicated question, but really, compared to medicines we use

       to treat bipolar disorder during pregnancy, the SSRIs are a

       relatively comfortable group. So, sorry for the long … it’s a

       question that takes a long answer.

                  WOMAN: Thank you.

                  KATHERINE WISNER, M.D.: The exposure through

       breast feeding is orders of magnitude smaller than during

       pregnancy. The benefits of breast feeding certainly well outweigh

       any exposure of any of the commonly used SSRIs.

                  JEFFREY A. LIEBERMAN, M.D.: It sounds like it boils

       down to the risk for an individual woman of not taking medication

       and risking recurring depression versus the exposure to the fetus

       to this possibility of some effects, albeit very small.

                  KATHERINE WISNER, M.D.: Yes, exactly, with a caveat,

       though, that we really want to have other tools. So for example,

       one of the studies we’re doing is transitioning women who would

       prefer to be off meds to cognitive therapy while they’re tapering

       their meds, and looking to see if maintenance cognitive therapy
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       can sustain them during pregnancy. That’s not been done either.

       But that’s like a lot of this work. It’s all pretty novel.

                  JEFFREY A. LIEBERMAN, M.D.: Yes, sir.

                  MAN: Short question.

                  JEFFREY A. LIEBERMAN, M.D.: Good. We like short


                  MAN: Yeah. On the People’s Pharmacy this morning, the

       public radio show, Joe Graedon mentioned omega-3 fatty acids for

       depression in the context of its use for some cardiovascular

       disease. You hadn’t brought that up, and between the omega-e,

       the DHA, that seems like it could have very multiple benefits, but

       without negative consequences.

                  KATHERINE WISNER, M.D.: Right. So what about

       omega-3 fatty acids, fish oils? We have been doing some work

       with a colleague, Marlene Freeman, now for many years, to look at

       fish oils and its potential use for treatment in pregnancy. So

       there’s a literature in non-pregnant patients that suggests that for

       depression, omega-3s have usefulness to treat depression in

       some patients. And there’s, I think, even more exciting research

       about prevention of the development of psychotic episodes when
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       it’s used preventively.

                  Just going back to pregnancy, you have to use fish oil in

       the naturally occurring ratio of the various essential fatty acids

       during pregnancy, because if you use one in high dose, it

       destabilizes the ratio. There are some reports of poor fetal

       outcomes. So you have to use fish oil. We looked at various

       doses of fish oil during pregnancy, and there are many reasons to

       use fish oil, including visual development, intellectual development,

       other reasons to use fish oil during pregnancy. Thus far, we were

       unable to show that supplemental fish oil added additional benefit

       for depression on top of a supportive therapy control group. It could

       be a sample size issue, and certainly their recommendations that

       Marlene and an APA work group that I was part of, we made the

       recommendation for supplementation for fish oil. So I think it’s a

       very good thing. Many reasons from a health standpoint to use it. I

       take two grams a day for cardiovascular risk protection. But as far

       as hard evidence that it can treat depression in pregnancy, we’re

       still awaiting that.

                  JEFFREY A. LIEBERMAN, M.D.: That’s a very important

       point that applies to a lot of what are called complementary and
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       alternative medicines. They sound good. They don’t appear to

       have any real significant risks, but the evidence to prove that they

       actually work in the way that it’s suggested has to be demonstrated

       first. Yes, Ma’am.

                   WOMAN: With women getting married later and starting

       families later in life, do you look at the age of the mother for first

       time pregnancy? Is there any difference in the occurrence of

       depression, whether the mother is younger or older?

                   KATHERINE WISNER, M.D.: Actually, we have looked at

       that, and we don’t really find a difference. So our average age in

       our sample is about 29. We have a real span. Now, when I say

       that, I’m talking about a span, 18 and up, because the adolescents

       are a somewhat different group. There’s a difference in the

       number of episodes, often, that a woman has, if she’s older,

       because she may have already developed recurrent depression.

       But the likelihood of developing postpartum depression, other than

       the first pregnancy, where it’s higher, doesn’t seem to be that


                   One unanswered question, though, is what about the risk

       for postpartum depression in women who use assisted
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       reproductive technologies? That’s really not a well studied

       question, and just clinically, I believe there is a relationship there,

       that there’s an increased risk. But I’m not sure if that’s because

       whatever resulted in the infertility might be in fact connected to

       mood problems, or some physiological … but there does seem to

       be risk, and that’s an incredible need for research.

                  WOMAN: Interesting. Thank you.

                  JEFFREY A. LIEBERMAN, M.D.: Let me just mention

       that because of the interest in the topic, we’re going to take a few

       more question. But it’s going to cost five minutes of the break. I

       just wanted people to be aware of that. (Laughter) Yes, sir.

                  MAN: Yes. Lactating women have a lowered estradiol,

       and elevated prolactin. Therefore, in your studies of the effect of

       estradiol for depression, will you be separating lactating women

       from non-lactating women?

                  KATHERINE WISNER, M.D.: Yes, good, good question.

       So there are a whole number of issue here. One is, estradiol

       supplementation could possibly reduce the breast milk secretion by

       the mother. So one of the issues we had to deal with is, well, what

       is the evidence that that’s the case? So up to 100 micrograms, the
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       estradiol does not appear to suppress lactation, the volume of

       breast milk. But we go up to 200, so we have this very

       complicated breast milk, feeding collection, analysis for estradiol,

       baby weight protocol in this study to answer that question about,

       are we potentially compromising the baby’s nutrition?

                  The second question is, well, what about breast feeing

       women themselves? They’re different than women who don’t

       breastfeed. Is breastfeeding a predictor of potential response or

       nonresponse? So, yes, we are looking at that very carefully in the

       study. The final comment I would make about breastfeeding is that

       we don’t know a lot about breastfeeding, and one of my pediatric

       colleagues is looking at this. What I mean by that is, we’re

       studying all these hormones, and getting all these measures and

       all these data for breastfeeding.

                  So what bothers me about that is, breastfeeding is a word

       that describes an action. So we have women who say

       breastfeeding is … God’s gift to women, mother earth, this is

       fabulous. Which creates a different kind of cognitive set. And then

       we have … I hate this. The only reason I’m doing it is my

       pediatrician says there’s allergies in my family, and he made me
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       feel guilty. I have to do it. And my husband says you’ve got to

       feed the baby because it’s better. You’ve got to breastfeed. And I

       hate it. With an entirely different cognitive frame.

                  So we’re collecting all these sophisticated measures, and

       one of the things we’re trying to do is understand, beside the

       action, what the cognitive frame of the woman is with

       breastfeeding, because that may actually have more of an impact

       than just breastfeeding itself. So I appreciate the question,

       because it’s a very good one.

                  JEFFREY A. LIEBERMAN, M.D.: I have to limit it to just

       two more question. This woman, and this woman. Yes, Ma’am.

                  WOMAN: Thank you. In response to the bright light

       therapy, are there hours of the day that is optimum, and hours of

       the day where it doesn’t matter?

                  KATHERINE WISNER, M.D.: With the bright light

       therapy, there are very good data to implement the light for

       unipolar depression at an optimal time of day for that individual

       person. One can determine that, free, on a website, www.cet.org.

       It stands for Center for Environmental Therapeutics. It is located at

       Dr. Lieberman’s facility at Columbia. It’s Mike Terman’s website.
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       So it will ask a series of questions about sleep and awake habits,

       and that algorithm will yield an optimal time of light therapy in the

       morning, for an individual. So there are ways in which you can

       make sure that you’re using that bolus of light at an optimal time for

       you. That’s for the artificial light therapy treatment. The usual time

       is, start with a half an hour, and it’s best to do it as soon as

       possible, after you get out of bed. So those kinds of things have

       been worked out, yes.

                  WOMAN: For those of us who are past childhood bearing

       age, and are still dealing with depression, which may or may not

       get worse as time goes on, I’d like to know what your input is about

       medication … it’s a medical food called Deplin. I take 7.5

       milligrams. And I want to know, does it really work? My

       psychiatrist says, well, maybe it does. And what’s happened in the

       past couple of months is that the insurance companies now have

       gone from $45 a month to $75 a month. Is it worth it?

                  KATHERINE WISNER, M.D.: Ah, good question. So this

       hearkens back. I actually have a masters degree in nutrition from

       way back, where I’ve always been interested in how can we

       ensure that the brain is well nourished enough, so that whatever
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       treatment we put into it, that it can respond optimally? Deplin is

       one like that, that has a lot of mixed information, a lot of data to

       suggest that its use … it’s a concentrated folate compound, that it’s

       use prepares the brain, if you will, for better responsivity to other

       treatments. This is sort of like what you were saying before,

       where, if you look at the data all together, there’s not a real

       convincing picture yet. So let me go to anecdotally.

                  There are a number of patients that I have seen who

       really don’t have a particularly good response, and don’t pay the

       money. There is a patient who I know quite well, say, my sister,

       who has bipolar disorder, who has taken it after a fairly unstable

       period of mood instability, and she is on it, and it does seem to

       make a difference for her. So I tend to think about this as an N of 1

       trial. Let’s set up some careful markets. Let’s see what it impacts

       for you, whether it’s sustained, because it is expensive. But a lot of

       our drugs are expensive.

                  My guess is that we have these diseases, and we say,

       people have these diseases because the symptoms we see are

       similar, but what’s really happening in the brain? I’m sure that

       we’re incredibly heterogeneous, so that Deplin, for some subset,
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       may be a miracle. For others, it may not work at all. I don’t think

       we’re particularly good yet at personalizing medication treatments

       or other treatments. That’s in fact one of the parts of the strategic

       plan for NIMH as well, to do more personalization, figure out who

       should pay the 75 bucks, and who shouldn’t.

                  WOMAN: Okay. Than you very much.

                  JEFFREY A. LIEBERMAN, M.D.: So for these kinds of

       treatments that … these are newly emergent. What we desire is

       definitive evidence which indicates that they work. In the absence

       of definitive evidence that they don’t work, in the absence of that,

       we have these sort of anecdotal personal examples that we can

       rely on, and it appears this one sort of falls in the middle there.

       Okay, thank you very much, Katherine.

                  KATHERINE WISNER, M.D.: Thank you.


                  JEFFREY A. LIEBERMAN, M.D.: So we’re at the midway

       point. We’re going to take a break for 15 minutes, and return here

       around 11:15 to hear Dr. Fred Volkmar about autism.

                  (Background Conversation)

                  (PART THREE)
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                  JEFFREY A. LIEBERMAN, M.D.:

       Okay, if we could ask the people out in the foyer to come back in

       so we can get started? It wasn’t too long ago when the word

       developmental disabilities, autism, autism spectrum disorder,

       Asperger syndrome was practically unknown within the medical

       field and within the population at large. But now, it’s emerged as

       one of the most compelling public health problems for the country.

                  (Background Conversation)

                  JEFFREY A. LIEBERMAN, M.D.: Is my mike on? In

       conclusion … (Laughter)

                  (Background Conversation)

                  JEFFREY A. LIEBERMAN, M.D.: Our next presentation

       is one of the most compelling public health problems in the United

       States and the world today, and we have someone to speak to us

       who’s been involved with its study and treatment for most of his

       career, and is one of the leading experts in the field of autism and

       intellectual disabilities, Dr. Fred Volkmar. Dr. Volkmar is the Irving

       B. Harris Professor of Child Psychiatry, Pediatrics and Psychology

       at Yale, and Director of the Yale University Child Study Center. So

       please join me in welcoming Dr. Fred Volkmar.
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                  FRED VOLKMAR, M.D.: Thank you very much. Good

       morning, everyone. So, here we go. Let’s see if we can get this to


                  (Background Conversation)

                  FRED VOLKMAR, M.D.: Mike. Mike. Ah, mike. I think

       the mike’s working. I hope the mike’s working. Yes. Now let’s see

       if I can make this happen. Am I pushing the right button? I push

       the button and nothing happens.

                  (Background Conversation)

                  FRED VOLKMAR, M.D.: Hey. Now we’re cooking with

       gas. I was once giving a talk in Kansas, and you’ll see the

       association in a second. And the people, of course, I grew up in

       Illinois. Everyone’s very polite. I’m sure it’s the same in Florida.

       And in Kansas, they’re really polite. It’s not true in Massachusetts.

       But it’s interesting. You can tell by the drivers, actually. I was just

       talking to somebody about driving. But in Kansas, the people were

       so polite, and then there was a screen behind me like this, and I

       was showing some movies, and I’m giving my talk. It was going

       fine, until I started showing the movie, and I’m talking, and the
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       people are sort of staring, and I hadn’t realized the movie was

       displaying. This went on for about five minutes before somebody

       very politely came up to me, said, they don’t see the movie.

       Anyway, if you don’t see the slide changing, please let me know,

       because it’s behind. I can watch down here, so I’ll see a little bit of

       it, I hope.

                  I need to disclose my conflicts, which are some grants,

       some books, some journals. And also this book, which I’m going to

       come back to talk to, which my wife, who’s a pediatrician, and I did,

       really partly to get some information out to parents. In some funny

       sense, that’s the take home message of this talk, is I want to say

       that there’s more and more good information out there for parents

       and teachers.

                  I want to start off with some paradoxes, autism then and

       now. Autism was once thought to be relatively rare. It’s not

       actually thought to be relatively common. That’s true if you take a

       broad view of the matter, if we talk about autism spectrum

       disorders. It gets a little confusing for people, they say, oh, autism

       has increased dramatically. Well, actually probably classical autism

       is probably pretty much around where it always has been, which is
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       one … maybe 800 to a thousand children.

                  The broader spectrum of autism disorders is more like

       150. And when you hear the ads on television and they’re saying

       one in 150, they’re talking about this broader spectrum of autism

       and related conditions. We also now are much closer in terms of

       the biology of autism, having really good leads in terms of genes

       that we’re going to be able to trace back to the brain, and

       behaviors. So it’s a very exciting time in terms of autism research.

                  Autism was once thought to be congenital. Interestingly,

       we’re now diagnosing autism earlier and earlier in life. We do see a

       few children who develop autism after some time, normal

       development, and one of the things in terms of research that’s

       clearly going to be happening over the next few years is an

       increased focus on understanding basic brain mechanisms. So

       the kinds of things that we’re interested in have been reflected by

       the tremendous increase in publications over the year.

                  The last year that I have full data available, 2008, over

       one thousand peer reviewed papers on autism, research papers.

       When you think about what a tremendous increase this is, that’s

       just amazing. We’ve had improved outcome that I want to talk
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       about. I’m going to say a little bit about some of the advances in

       genetics and neurobiology.

                  In terms of neurobiology, there have been a number of

       interesting findings in terms of how the brain works. Probably the

       first thing we understood about autism was the high rates of

       seizures that sort of implicated something about the brain. As

       people have gone on and looked, they discovered very interesting

       things about early brain development. Many toddlers with autism,

       for example, turn out of have very large heads, which we hadn’t

       appreciated. It tends to develop in the first year of life.

                  A colleague down at University of Louisville, Manny

       Casanova, and this is one of his slides, has actually talked about

       how there may be some changes in the brain that account for that.

       It’s a failure, perhaps, of the normal pruning of neural cells, the

       connections to each other. So it’s as if you pick up the telephone

       and instead of talking to your neighbor, you’re talking to a thousand


                  There are also interesting things in terms of looking at

       brain aspects like certain kinds of neurons, work on the faces. We

       now understand something more about how children with autism
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       look at faces. They tend to see faces in a different way than the

       rest of us. They look at faces like they look at other objects.

       Interestingly, one study by a colleague of mine at Yale has found

       differences in the placentas of children with autism.

                  Outcome issues. I want to say a little bit about outcome

       to frame some of the things I want to say about treatment. If you

       look early on, there was a lot of confusing about autism. It’s hard to

       know much about what was being said about outcome. Over time,

       things have changed. One of the important things to realize in this

       country was, there was a law, public law 94-142, which, for the first

       time established for children, all children, the right to a free and

       appropriate education.

                  This was a landmark. The reason it was a landmark in

       autism, before that law was passed, probably only about 20

       percent of children with autism got a public school education. And

       you see what happened to them? Their parents were told by the

       school districts, put this child away. Put them in a residential

       center. Put them somewhere, a state home. So what happened

       was, the children learned how to live in a state home. With public

       law 94-142, for the first time, there was as tremendous push
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       towards intervention.

                  Now, I also want to say, just to qualify this before I show

       you some of the outcome data, I’m going to be talking about

       classical autism, which is not the same thing as the broader

       spectrum, and I’m not talking about Asperger’s. I’ll say a little bit

       about Asperger’s shortly. But there’s some issues in terms of

       thinking about treatment, and thinking about some changes over

       time. The definition I’m going to use here is for good outcome

       means you’re independent as an adult. You’re fully self sufficient.

       Fair means you need some assistance. So you’re partly self

       sufficient, but not totally. And poor pretty much means 24/7 care.

       These are children who are in residential programs as adults.

                  Cherry picking results, and you’ll see why in a second,

       this is the first set of outcome studies on autism, classical autism.

       You can see here the studies that go from 1956 to 1974. This

       would have been before public law 94-142. This would have been

       before. Most children were getting educational and other

       interventions. You can see the number of good outcome here,

       about five percent of children with classical autism, in adulthood,

       were independent and self sufficient.
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                  Here is another set of studies. I’m cherry picking later.

       This would be the first wave of children seen after that law. Again,

       they wouldn’t have necessarily had the full effects and the benefits

       of earliest diagnosis, but we’re starting to see some ripple effects

       of intervention. Now look at the number of good. About 20 to 25

       percent. That’s fantastic. There’s good reason to think this

       number is continuing to change over time, which is actually a very

       hopeful thing.

                  There’s some very good resources in terms of treatment.

       Probably if you’re a parent or a teacher and you wanted something

       really good about treatment, this book from the National Research

       Council, which is called Educating Children With Autism, costs

       about $30 on Amazon. It was put together through an independent

       government commission from the National Research Council. It

       makes the point that for early intervention in autism, we know a lot

       about what works.

                  Now, I have to emphasize, and I know some parents have

       come up to talk to me about adult children, interesting, most of the

       treatment literature is focused on very young children. One of the

       needs we have is to be able to look at treatment issues in
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       adolescents and adults. But this book focuses on young children,

       and it makes some points about what works and what doesn’t work

       in autism. It talks about how important structured intervention is. It

       says there are many different programs that seem to work. They

       have many things in common. And a few areas of difference. It

       also makes an important point. I was talking to one parent today. It

       says that not every child gets better, even in good programs. We

       need to understand why some children don’t respond so well to

       good programs, while other children do. We also have increasingly

       good drug studies. I’m going to show you the examples of one of

       those in just a second.

                  If you want to understand our model basically of autism

       and understanding treatment, this is the model, on the next two

       slides. In a funny way, it’s the take home message from this talk.

       Autism is a disorder that impacts negatively on development. I’m

       going to show you some slides later on from some of our eye

       tracking work. I would suggest that people with autism might take

       in maybe ten percent of the information the rest of us take in, in

       ongoing social interaction. So it’s like they have glasses on to filter

       out all but a little bit of the sunlight. So that’s the problem.
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                  That interferes a lot with learning. If you’re sitting in a first

       grade class, and you’re watching the teacher and taking your lead

       from her, if you’re typically developing, you’re a very effective

       learner. You’re organized. You’re paying attention. You’re

       focused on what she or he is saying. You’re taking it in. If you’re a

       kid with autism, the lights, or the rug, or the walls, or any of a

       number of different things might be equally or even more

       importantly relevant to you. So it’s a real challenge. So from the

       point of view of intervention, well, I’ll show you what we want to do,

       which is this. We want to minimize the negative effects that autism

       has on early learning. We want to maximize, as much as we can,

       the ability of a child to develop and grow normally. That’s the

       bottom line. We seem to be able to do that to some degree.

                  As I mentioned, we actually now have some good drug

       studies. This is a double blind, placebo control, the best kind of

       drug study, looking at risperidone, which is a medicine which a

       very powerful medicine. But this was a double blind study, and it

       was used to treat children who had horrible problems with

       agitation, anxiety, and they were upset, and it interfered with their

       program. And by two weeks, you can see that the active treatment
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       group was significantly improved compared to the other group.

                  Now, how to understand improvement? Well, we think

       there are several things that are involved. As I mentioned, this is a

       moving target, which is a happy problem, because it’s moving in a

       good way. But it’s also a complication for researchers in terms of

       who we studying and trying to think about what we’re looking at.

       Clearly, we’re seeing more and more interest in early diagnosis of

       autism. I’m going to show you some data on that shortly. We’re

       not able to routinely see children that we’re concerned about

       before a year of age. We can’t absolutely say that the child has

       autism, typically, until around age three. But we do think that we’re

       actually doing a better job of identifying children earlier, which

       means we can also intervene earlier. There’s some reason to think

       that the earlier we intervene, probably the better.

                  Now, we still don’t understand issues of mechanisms.

       How does this really work? What’s the most effected(?) part?

       How much is enough? Is ten hours of ABA enough a week? Is it

       20 hours? Is it 40 hours? We still don’t know, and that’s an

       important question. As you heard Dr. Lieberman say, we have a

       real need to think about personalized treatments at a very high,
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       sophisticated level. The question in autism is, how do you match

       the child to the treatment? How much does this child need?

                  We also know that we’re doing a better job of looking at

       interventions. We have well controlled studies now, both of things

       like risperidone. We have some studies of the SSRIs. We have

       very good data on behavioral treatments. Now, we also know that

       treatment studies are some of the most difficult to do. For those of

       you in the audience who are like me, who are researchers, the

       interesting thing is, we used to serve on study sections at the

       federal level, and we were reviewing grants.

                   When you see a treatment study, I sometimes describes

       those as wounded ducks in the water. You can kill them with your

       oar; because it really only takes on person these days to kill a

       grant, often in the study section. And treatment studies

       intrinsically, they’re like oriental rugs. They always have a flaw.

       You can’t have a perfect treatment study. I’ve never met one. But

       it’s a problem, and it’s a problem because I think the most effective

       treatment studies we’ve had have basically been, unfortunately,

       imposed on us by the federal government.

                  There have been these sort of collaborative studies, the
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       federal government said okay, we’re giving you money. You’ve got

       to do this study. In some sense, that’s not a bad strategory(?),

       because it gets the study on. On the other hand, it tends to bring

       the science down, I think, a certain notch in terms of what

       everyone can agree on. So it’s an interesting problem.

                  For more able children, and several people came up to

       talk to me about children and grandchildren with Asperger’s. Often

       the complaint is the child’s too bright, or too verbal. People don’t

       see the social disability, because the child’s talkative. Or the

       behavioral difficulties get into the way. Sometimes, and I don’t

       know what the labels in Florida are. These vary around the

       country. School labels, and medical labels are sometimes

       different. But there’s a set of these funny school labels, SEM, SED,

       ED, BD. People know what these mean? Socially emotionally

       maladjusted. Emotionally disturbed. Behavior disturbed. It means

       bad boys.

                  The trouble is, yes, the behavior is a problematic thing,

       and you have to focus on the behavior. But, what it can mean is,

       you take a child who’s socially very vulnerable, often actually rather

       socially naïve, and often well meaning in some ways, and you put
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       them in a special class for really bad boys. Then typically, in about

       five seconds, all hell breaks loose. I have literally had a first

       grader, a kid with Asperger’s, who was put in a class for really bad

       behavior disturbed boys. Five minutes, another kid in the room

       said, hey Johnny, you see that red box over there that says Fire

       Alarm? Go pull that and see what happens. And of course he did,

       because that’s what he was told to do. So another set of problems

       is often educating people about the underlying social vulnerabilities

       and what we can do about it.

                  Asperger’s differs from autism in some ways. Now,

       Asperger’s is a controversial, in some sense, diagnosis. It got put

       in in 1994 into DSM. It may or may not last into DSM-5, although

       it’s not impossible. DSM-5 will implode before that time. But it’s

       interesting, which itself is a discussion, but I think one of the good

       things about Asperger’s is, it points, as Asperger suggested, to

       kids, mostly boys, but sometimes girls, who have very significant

       social problems. But, their words are good. They have good

       verbalization. They have good vocabulary. Now, communication

       may not be so good. So the child may know everything about

       rocks, or dinosaurs, or American gangsters, or the Weather
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       Channel. And is talking about it all the time. But might not able to

       have a real conversation about it, because he doesn’t want to hear

       what the other person has to say.

                  It’s an interesting, again, problem because it’s often that

       verbalization, because oh, he can’t have autism. It disguises the

       verbal vulnerability. I think one of the important reasons to have

       Asperger’s as a category is that it marks a group of children who

       have a social vulnerability, but they’re verbal. It’s important, I think,

       for research reasons to also clinically, because it tells us we’ve had

       a handle. And what’s the handle? It’s verbal. Be explicit. Be

       explicit. Be explicit. Be very verbal.

                  I have one young man who wants to talk to ladies about

       their breasts. That’s a problem. (Laughter) You have to explain to

       him, no, no breast talk. He now goes up to a lady. He’ll say, you

       have a nice set of lungs, Ma’am. (Laughter) And it’s a little odd,

       but it’s better than what the alternative was. And we’re working to

       improve it. But it’s that kind of thing, that if you think about, you’re

       going to use the verbal strategy to help this child learn. You can

       teach. You also become aware of the learning style, which in

       Asperger’s is often, kids get little fragments of things, but with the
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       verbal abilities, you can actually use a strategy of going from the

       parts to the whole.

                  If any of you have ever seen, there’s a nice set of books

       that have all pictures but no stories. Have a kid with Asperger’s tell

       you the story. One of these books is called The Boy, The Dog And

       The Frog. The kid says, there’s a boy, there’s a dog and a frog.

       Turn the page. There’s a boy, there’s a dog and a frog. Turn the

       page. There’s a boy and a dog … okay. He’s not getting the story.

       So you go back and you say, okay, I want you to be a detective, or

       a reporter, I don’t care which, and the reason is, you want to ask all

       these pesty W-H questions. Who, what, where, when and why?

                  Amazingly, when you start to take that strategy, and

       again, because you’ve got the verbal ability, there’s a boy, there’s

       a dog and a frog. Don’t turn the page. Where are they? They’re at

       the lake. What are they doing? Oh, the boy’s got a net. Oh,

       maybe he’s trying to catch the frog. Okay. Already, it’s multiple

       steps up from just looking at who’s involved.

                  We also can do things like teaching awareness of

       feelings. There’s a lot we can do in terms of very focused CBT

       kinds of therapy. We also want to look at the academic curriculum.
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       In the interest of time, I’ll move along very quickly to show you an

       example. We have one boy who I’ve known for years and years

       and years, who has a real thing about snakes. He got to the

       seventh grade in Connecticut. His class is spending the whole year

       studying the Civil War. And they have a class project that … every

       student has to do a project for Parents Night, on one of the battles

       of the Civil War, and they have to have a map. And they have to

       know who the generals were, and what was involved, and they’re

       going to present this.

                  The teacher, and the mother and I had a wonderful

       discussion on the phone. The teacher said, I don’t know what

       we’re going to do. I’m teaching them the Red Badge Of Courage.

       He wants to see where the snakes are in the Red Badge of

       Courage. And he’s got to do this project, and it’s going to be a

       disaster, and he won’t have it done. And she said, oh, I wish only

       there were snakes in the Civil War. And I said, what a fantastic

       idea. This was part of the kid’s project. This is the snakes of the

       Battle of Gettysburg. (Laughter)

                  The kid followed all the teacher’s rules. Here’s Robert E.

       Lee, and here’s the map, and you can see where Robert E. Lee is
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       going to be in the map, and here’s a picture of the battle. And

       because he’s near the creek, what’s he going to see, but

       agkistrodon piscivorus, the dreaded water moccasin? But the

       interesting thing about this, the kid ended up learning a lot about

       the Battle of Gettysburg.

                  Again, treatment research, there’s a lot of interesting

       needs right now. We need better studies. We need better

       measures, especially for the drug studies. Our measures are really

       quite crude. We also need to understand more about who does

       and doesn’t respond, and we also need to expand from very young

       children to adolescents and adults, especially among adults.

       There’s a tremendous need for services, and often very few

       practitioners. Again, we know that the outcome is better. We think

       we are doing a better job of taking research finding into clinical

       practice, but again, we’ll have to see.

                  I think the last time I was here, I showed some of our eye

       tracking stuff. This is just to concretize, this is people with high

       functioning autism, Asperger’s, watching the movie “Who’s Afraid

       of Virginia Wolf?” The person who’s typically developing goes

       back and forth in about five seconds, looking at the eyes. The
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       person with autism goes back and forth with the mouth. If you use

       that as a strategy, like in this scene where something scary has

       happened, something scary has happened, the typical viewer goes

       straight to George Segal’s eyes to take in the fright. The person

       with autism goes to the mouth. The trouble with that is, about 90

       percent of the social affective information is contained in the top

       half of the face.

                  Interestingly, this turns out to be a very early developing

       issues. These are one year olds watching movies of other one

       year olds. We can’t show them Elizabeth Taylor in Virginia Wolf.

       But, you can see the typically developing child in the yellow, and

       the child we’re worried about autism, because it was a sibling.

       This is going back from the mouth to that pretty purple cup. Again,

       these differences in information processing develop very early on,

       and this part of the reason, A, that we like to get in there and

       intervene early, but B, it may help us think about screening, and

       more appropriate and faster ways to screen for risk for autism,

       even in the first months of life.

                  Interestingly enough, the question is not so much of

       course thinking about autism versus typical children; the question
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       is, can we differentiate autism in very young children from kids with

       developmental disability, mental retardation but without autism?

       And this slide shows that we can. This is some data that actually

       just came out. The green are children with autism. And the two

       yellows, there’s a light yellow and a dark yellow. The light yellow

       are the typically developing toddlers, same age. The light yellow

       are the children, the toddlers, but with development delay without

       autism. You can see that the differences here are very clearly

       related to the autism.

                  Moving on, treatment studies we’ve talked about.

       Translational research. One of the problems, and one of the

       reasons my wife and I were interested in writing this book, we need

       to do a better job of bringing what we know into the lives of parents

       and teachers in schools, and we think we have enough now that

       we can actually start to do that. There are several books in the

       work, including one on evidence based treatments in autism, which

       is fantastic.

                  We also know there are more and more things out there

       on the internet. If you type in autism on Google, you get 15 million

       hits. The trouble is, after about the first 100 or so good ones, your
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       yield goes down really fast. There are two studies right now that

       are being reviewed in the Journal of Autism. Interestingly, the top

       100 sites from multiple search engines, there are some problems.

       About a third of the sites are either advertising or selling

       something. Some new miracle cure. Or they have some vested

       stake. That’s not necessarily disclosed. So unfortunately, the

       internet, although it’s a wonderful resource, it’s also limited in some


                  There are more and more information sources out there. I

       mentioned the Journal of Autism, which I edit. We actually are

       going to have an autism encyclopedia with links back to peer

       reviewed research articles, which I think is fantastic. I mentioned

       the book on evidence based practice. Interestingly, for the last

       25years, I’ve taught a course in Yale College, not Yale University,

       but Yale College, for Yale students interested in autism. They go

       and work in a school, and they come and have a seminar. We just

       finished the last semester of videotaping all the lectures, and

       they’re going to be up, I think, next month on YouTube. There’s a

       Yale YouTube channel, and they’ll be free. I think 12, 15 lectures,

       genetics of autism, behavioral interventions, some of the leading
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       researchers. And, they’re in 40, 50 languages. Which is fantastic.

       We’ll hope. We’ll see how well this works.

                  In summary, there have been many advances in terms of

       autism. This is a very exciting time to be in research. Also,

       because for the first time, we’re actually being able to translate

       things into service. We do have some needs, which is thinking

       about bringing the science into the classroom, bringing the science

       into the home. Translating research in more effective ways.

       Developing better measures. Even things, for example, like the

       eye tracking, to use in drug studies would be very interesting.

       Nobody’s ever done it. But something, we’re not just paper and

       pencil things, where we actually have something we can measure

       in terms of the child’s performance to see, does it help them

       engage more effectively?

                  Finally, developing quality resources for parents is really

       important. I hope I’m just about on time. Good? So here are

       some of the references, and we have time for several questions.

       Thank you very much.


                  JEFFREY A. LIBERMAN, M.D.: Thanks very much, Fred.
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       So we have time for questions. Yes, Ma’am.

                  WOMAN: I have a question. Is there a ratio to boys to

       girls as far as autism?

                  FRED VOLKMAR, M.D.: Yes, that’s a good question.

       There’s some gender differences. They’re not much studied, but

       there is a little work on gender differences. Typically, the numbers

       are four to five times as many boys as girls. We think that probably

       relates to the genetics. It turns out similar numbers show up in

       language disorders, some other early onset difficulties. Girls are

       probably somewhat less vulnerable.

                  The flip side is, often as a group, when girls get more

       classical autism, it seems like they have more severe autism, and

       probably that’s because the genetics, it takes sort of a stronger hit,

       genetically. Among the more able people, boys vastly outnumber

       girls. When you see it in girls, it’s often very similar, but it’s maybe

       a little subtler, so it can be hard to diagnose sometimes.

                  WOMAN: And a flip to that. If you have an autistic child,

       what are the changes of your second child being?

                  FRED VOLKMAR, M.D.: The data on that are somewhat

       in flux. That being said, the earliest studies said the rate was
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       about percent. Which didn’t sound like so much, except when you

       think of autism is, one should think, one in 800, that’s a lot. Even if

       you think of one in 150 for autism spectrum, that’s a big increase.

       As people started to look, they realized that there actually were

       even stronger genetics. I would say at the moment, the risk is

       between one in 10 and one in 20.

                  WOMAN: Thank you.

                  JEFFREY A. LIBERMAN, M.D.: Yes, Ma’am.

                  WOMAN: What’s the prevalence of autism among

       cultural populations? And is there a difference between the

       environment as well?

                  FRED VOLKMAR, M.D.: The cultural issues, it’s

       interesting, are not much written about. That being said, I’ve seen

       kids with autism from every single continent except for Antarctica.

       And it looks remarkably the same. Now, how the culture thinks of it

       can be very different, and so there can be very significant issues in

       treatment, and there are interesting cultural things that can impact

       on this. In this country, children who are poorer and living in the

       inner city may be less likely to be diagnosed. There’s actually a

       good body of work on that. In some cultures, autism is not
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       something people want to talk about, so it gets called something

       else. It turns out to impact on the sibling’s abilities to marry. It turns

       out it’s a bad thing to have a child with a disability.

                  Other cultures have a very different kind of approach to

       children with disabilities. In Italy, for example, which I’ve been

       going to for a number of years now, the Italians, which are

       wonderful, wonderful people, their philosophy had been kind of,

       don’t interfere with anybody. If somebody wants to sit in a corner

       and body rock, let them sit in a corner and body rock.

                  The trouble is, if you have a four or five year old with

       autism, and that’s what they want to do, all they’re going to learn to

       do is to sit in the corner and body rock. When kids go to school,

       we don’t just tell them to sit and do whatever they want. We have

       a structure, right? So the parents in Italy, interestingly enough, got

       together and said, we need to do something more like the

       Americans. We need some services. So they’re kind of gearing up,

       and it’s requiring a culture shift.

                  There’s some cultures, interestingly, France, emerges, for

       reasons totally unclear, well, kind of unclear, historically, in France,

       mothers are blamed for the child’s autism. The standard, which is
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       what used to be done here in the fifties, so the standard treatment

       is, you separate the child and the mother, and there’s actually a

       lawsuit going on right now in France to say, no, no, we need

       services. Cut out this crap. We need services. So, sorry, a long

       answer to the question.

                  JEFFREY A. LIBERMAN, M.D.: And environment?

                  FRED VOLKMAR, M.D.: Oh, environment.

       Environmental factors in autism, interesting, there’s a tremendous

       amount of interest, but very little data. The strongest data are far

       and away the genetic data. There’s a little bit of work suggesting

       perhaps the increased risk in pregnancy, labor and delivery of

       children with autism, but, it turns out that most of that increased

       risk has to do with finding things that are a little odd about the child

       at birth. So it could also be that having some genetic vulnerability

       makes you a little more likely to have some vulnerability at birth.

       So surprisingly, there’s not much evidence in terms of

       environmental factors.

                  JEFFREY A. LIBERMAN, M.D.: Is the paternal age or

       maternal age (Inaudible Portion)…

                  FRED VOLKMAR, M.D.: Paternal age and maternal age
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       have both been … there are a limited number of studies. The

       problem is, especially as we look at the broader spectrum, and

       some of these studies have looked at broader spectrum as

       opposed to classical autism, you can imagine, and let’s take

       paternal age for example, there’s one study from Israel that said,

       higher risk of autism if fathers were older.

                  One of the problems is, if you were somewhat socially

       odd, not horribly socially odd, maybe it would take you a little

       longer to find a spouse. If that’s true, you’ve sort of built in an

       automatic bias that these may well be somewhat … of course, then

       they didn’t actually look at the fathers. They looked at the siblings,

       and they just do the age of the father. So it’s an interesting

       problem of thinking about there may be some bias in terms of the

       way the study’s done; and potentially, similarly with the mothers.

       But again, it’s an interesting question. There’s a tiny bit of evidence

       for, actually on season of birth in autism, although most people

       actually haven’t been able to substantiate that in terms of looking

       at time of year.

                  JEFFREY A. LIEBERMAN, M.D.: Yes, Ma’am.

                  WOMAN: Hi. Can you hear me?
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                  FRED VOLKMAR, M.D.: Yes.

                  WOMAN: Oh. Can you tell me, in the case of a child with

       mild autism, is it better to mainstream them or to send them to a

       private school, and what kind of teachers are educated in autism?

                  FRED VOLKMAR, M.D.: Two good questions. The first,

       the answer is a little bit like my grandmother used to say about her

       sponge cake, which is, you bake it enough, it’s done but not

       burned. So the problem, especially for a somewhat more able

       child, is thinking about what’s the best match? There’s reasonably

       good data to say that if at all possible, exposing children to typical

       peers is a good thing. Typical peers, especially if you do a little bit

       of preparation, can be very effective teachers. There actually are

       some good curricula that talk about how you make peers more


                  Now there’s a risk, too, which is bullying, and that often

       happens as kids get older, but in general, if a child can go to a

       typical setting, you want typical peers involved, because it’s a way

       to learn. It’s a way … and typical peers can be just amazing. You

       watch a three or a four year old who’s prompted, intervene for a

       child with autism, they’re on it. They’ll be furiously engaging the
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       child. The child wanted to do … no, you’ve got to play with me.

       You’ve got to stay with me. You’ve got to talk to me. That’s one of

       the curriculums that actually is called stay, play and talk with your

       buddy. It’s not very fancy-shmancy for three and four year olds,

       but it’s very effective.

                  Back to teacher preparation, there’s a little bit of work

       around the country on teacher preparation. There are some

       courses that people are now doing. As I say, we’ve actually, I think,

       probably got like the longest standing one in the whole country on

       autism. Go figure. We don’t have a school of education. But it’s

       an area of real emphasis, I think, and there are tremendous

       variations from state to state. Some states have wonderful

       statewide models, Delaware and North Carolina. There, actually,

       there’s a fair amount of teacher preparation and work in the

       schools. Other states, it’s much more variable. Hopefully, with the

       current Administration, there’ll be a little more interest, and this is

       an area of work, can tell you, there was vanishingly little in the

       previous eight years.

                  WOMAN:          Thank you.

                  JEFFREY A. LIEBERMAN, M.D.: Yes, Ma’am.
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                  WOMAN: I’m wondering if you see any relationship

       between the negative symptoms of schizophrenia and autism?

       And there’s a lot of research being done now in autism, I think,

       because the parents have been so vocal and so active. I’m

       wondering if some of that research can translate into helping

       people with schizophrenia with those social problems.

                  FRED VOLKMAR, M.D.: It’s interesting. There are two

       things. One is, when people have looked, early on, there was a lot

       of confusion. Maybe autism was a kind of schizophrenia. It took

       people quite a while to sort that out, and we’re going to hear about

       schizophrenia shortly. The interesting thing is, when you look

       among adults with autism, the rate of schizophrenia, as it usually

       would be defined, is about the population rate. So it doesn’t look

       like it’s increased.

                  Now, that being said, doesn’t mean you can’t see it. You

       can. But there’s no reason to think you’re protected from it. But it’s

       not like … more of it. Other things, depression, actually is a

       different story. There probably are much higher rates of

       depression among more able people with autism, interestingly

       enough. We have good treatments for that. But that’s the negative
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       symptoms, the kind of lack of interest, that kind of stuff.

                  JEFFREY A. LIEBERMAN, M.D.: (Inaudible Portion)

                  FRED VOLKMAR, M.D.: In fact, yeah, the socialization

       issues, some of the same interventions probably could be used to

       work, and there’s a whole range of things. I was mentioning to

       several people, there’s some wonderful technological things.

       There’s some great new websites. There’s an app for the iPhone,

       iPod, called iPrompts. iPrompts, to a child who is nonverbal or with

       limited language, you can actually call up in the app, pictures, I can

       walk the child through various things like bathing, toileting, going to

       the bus. So there’s a lot of stuff that actually probably would be

       quite applicable.

                  JEFFREY A. LIEBERMAN, M.D.: Yes, Ma’am.

                  WOMAN: In the time when schools are standardized

       testing, and all schools have to give the same test throughout the

       country, the schools have to pass or fail, when you have a middle

       school kid, how do you get the teachers to let him do what you did

       with the snakes? As a parent, he can’t necessarily write what they

       want him to write, but he’s very bright, and could get it … how do

       you get teachers in the school system to allow them to do it their
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       way, to show their intelligence?

                  FRED VOLKMAR, M.D.: Well, of course, the first thing is,

       you want to be sure the child is eligible for special services. If the

       child has an IEP, an individualized educational plan, you can

       actually build in all kinds of things like accommodations, and they

       have to be reasonable. But you can build things in. If you don’t

       have an IEP, so the next level down is something called a 504

       plan, which is a little less detailed. If you don’t have that, they really

       don’t have to do much. Even if you have an IEP …

                  WOMAN: Yeah, even with an IEP …

                  FRED VOLKMAR, M.D.: … if you’ve got a bad school

       and/or a bad teacher, you’re in trouble.

                  WOMAN: Yeah, even with an IEP there’s …

                  FRED VOLKMAR, M.D.: That being said, there’s some

       wonderful educational consultants, and I think for some time, you

       know, people go into teaching usually for good reasons. It’s not

       because they want to be bad people. So I think often, if you can

       kind of help the teacher get her or his head around, the notion of,

       there’s something we can do as a minor accommodation that can

       make a major change for this kid, often they’re willing to think of it.
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       But you’re going to have some of the most bizarre battles.

                   I can remember one fight with some teacher at a PPT

       meeting, in Connecticut, with a little boy with Asperger’s, who had

       horrible writing problems. I suggesting giving him a laptop. Oh, this

       was … oh, I can’t give him a laptop. It’s a crutch, it’s a crutch,

       you’re giving him a crutch. And she was going off on this jag about

       a crutch.

                   WOMAN: Yeah, that’s what I (Inaudible Portion).

                   FRED VOLKMAR, M.D.: And I said, Ma’am, you know, if

       you didn’t have a leg and I gave you a crutch, it would be a

       mitzvah. (Laughter)

                   WOMAN: Exactly. The (Inaudible Portion)

                   FRED VOLKMAR, M.D.: You were sucking up, right? But

       it’s that kind of thing, but it takes a little education. I have a

       colleague who says, you can always wake somebody who’s

       asleep, but you can never wake somebody who’s pretending to be

       asleep. If the teacher doesn’t want to hear it, they won’t hear it.

                   JEFFREY A. LIEBERMAN, M.D.: We only have time for

       two more questions. Over here, and then over here.

                   WOMAN: I just want to thank you for all of your output,
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       number one, because for those of us who have an autistic family

       member, it’s tremendous, and very early understood, and thank

       you to NARSAD for funding some of our output, because it really

       helps us out a lot.

                  FRED VOLKMAR, M.D.: Thank you.


                  WOMAN: Can you talk about where they’re heading,

       maybe, with autistic spectrum disorders, and the new DSM-5

       criteria and how that’s going to come about?

                  FRED VOLKMAR, M.D.: We were actually just having a

       discussion of this at dinner last night. I’ll try to put it very

       diplomatically. (Laughter) It’s a very different process. I actually

       was part of the process for a while, and I resigned because I felt

       uncomfortable with the process. Another person who was involve

       last time, a wonderful epidemiologist, Jane Costello, also resigned.

       We’ll see what happens.

                  It’s a funny process in that last time it was more focused

       on peer review papers. It’s just very different. This time, and the

       thing that kind of tipped me over the edge at the end was, they

       floated(?) the notion of getting rid of Asperger’s in the New York
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       Times, as sort of a test. I said, what do you mean, publishing in

       the New York Times?

                  JEFFREY A. LIEBERMAN, M.D.: The short answer is,

       we don’t know. We’re hoping for the best.

                  FRED VOLKMAR, M.D.: Yeah. So it’s a problem. It’s a

       little bit floundering around. We’ll see if it can kind of reassert itself.

       But one of the worries, and I didn’t show you, I have slides that

       show in terms of the output of research, you worry if you vastly

       change the system, how are we going to understand who’s being

       studied? I think losing Asperger’s is unfortunate, but again, they

       want to go to autism spectrum. The paradox with autism spectrum

       as it’s currently defined, it’s pretty classical autism. So that

       although they change the name, in fact, if anything, they’re making

       it probably even harder, which is as little counterintuitive. That’s

       my take on it. So it’s a mess at the moment.

                  JEFFREY A. LIEBERMAN, M.D.: Nothing’s been formally

       decided, and if you have input, it’s open for comment, so you

       should definitely weigh in.

                  FRED VOLKMAR, M.D.: There’s a website, actually,

       DSM … we could figure out what the website is, but there is a
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       website you can go to. But again, I think that’s a funny way, that’s

       a good news and bad news story. I think it’s wonderful they want

       comments. On the other hand, it’s popularity that’s going to decide

       these things.

                  JEFFREY A. LIEBERMAN, M.D.: The basis for the

       diagnostic decisions should be very rigorous evaluation of data,

       scientific data. Yes, Ma’am.

                  WOMAN: A question regarding the use of ABA in

       resistance that some school systems have in working with ABA.


                  FRED VOLKMAR, M.D.: It’s interesting. If you read that

       report from the National Research Council, of the ten programs

       around the country that have good data showing that they work,

       many, probably most, are ABA based, but not all. Some are more

       sort of developmentally based. There are some, like the TEACCH

       Model in Chapel Hill, North Carolina, that’s more eclectic. But

       there’s good data to say that ABA works.

                  It’s interesting. The school sometimes will go off. They’ll

       follow one tangent. They’ll follow one track. They’ll say, oh, we’re

       going to have a Greenspan model, or the Sally Rogers
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       developmental model. I don’t necessarily disagree with that. I think

       the problem is matching the child to the treatment they need. For

       children who are lower functioning, and who are really

       disorganized, they really need a lot of help, focusing, attending,

       learning basic, learning to learn organizational skills. ABA is


                  Now, for a child who’s more able and who’s producing all

       kinds of things you can use in teaching, it’s not that it’s irrelevant,

       but it’s much less relevant than sort of following the child’s lead if

       you possibly can. So I think again the question of helping schools

       understand that there are a range of good models, and the

       challenge is coming up with a model for that child that works, which

       is what the law mandates.

                  JEFFREY A. LIEBERMAN, M.D.: This lady has been

       standing so patiently. Why don’t we take one last question?

                  FRED VOLKMAR, M.D.: Okay.

                  WOMAN: (Laughs) Oh, I appreciate this. I have been

       disturbed in the recent past, with some new mothers, or mothers to

       be, who claim that if you have your baby receive the shots that

       they are supposed to have after they are born, that they will get
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       autism, and they are staying clear of getting these shots, which I

       have heard this is happening in Europe, and they’re getting these

       illnesses, like measles, etcetera, and it’s slowly creeping in. I

       asked this one mother, I said, well, your child has to have these

       shots before they go to school. And she says, well, I found a

       doctor who’s going to let me get by with that.

                  FRED VOLKMAR, M.D.: It’s a very good question,

       especially for me and my children.

                  WOMAN: It’s right here in Palm Beach County.

                  FRED VOLKMAR, M.D.: Yeah. If you’re interested, and

       of course the problem is, you ask a professor, they always tell you

       the name of a book. There’s a very good book called False

       Prophets, by a name named Paul Offit, who’s one of the people

       who invented one of the newer immunizations. He talks about this

       whole issue. This started many years ago. There was a paper in

       the Lancet, a prominent English journal, that said children with

       autism seem to develop autism after they got the measles-mumps-

       rubella shot. That paper actually has been … was now withdrawn.

       There was just a lot of controversy over it. Nobody else has been

       able to find this. The paper itself was withdrawn by the Lancet not
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       very long ago. There’ve been multiple studies. People haven’t

       seen this.

                  On the other hand, we do know two things. One is that

       the public health benefits of immunizations are dramatic in terms of

       childhood, children not having measles, mumps, rubella, the kinds

       of things when I was a kid, kids had and died from. And

       sometimes were brain damaged from. Countries like in England,

       where they had this problem with stopping giving the shots, they

       actually are seeing now epidemics of measles and mumps, even

       mumps more importantly than measles, again, both preventable


                  The other thing I was talking to Paul Offit, he came up to

       give grand rounds for us, and he pointed out that in the olden

       times, probably many of the people in the audience like me had a

       smallpox vaccination. Remember that? The scratch on your arm?

       The so-called antigen load, because people say oh, they’re getting

       so many shots, it’s too much shots, the load from that one thing

       with the smallpox in the old days was so impure, it was probably

       about a thousand antigens. These days, kids get like 25 or 30,

       even though it’s multiple shots. So in fact we, the older folks, had
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       more of a kind of burden of the immunizations, and the kids these

       days, if you can follow that, so it doesn’t make much sense.

                  JEFFREY A. LIEBERMAN, M.D.: Thanks very much,


                  FRED VOLKMAR, M.D.: Thank you.


                  (PART FOUR)

                  JEFFREY A. LIEBERMAN, M.D.: We have a very special

       speaker who’s going to present to us next. Who is that? Oh.

       That’s me. I’m going to talk about schizophrenia. Do you want to

       advance the slide? Okay. This is a very famous photograph to

       students of medicine and psychiatry, which depicts what was

       called Asylum Inmates. This was taken at the end of the 19th

       century, and it really reflects what happens, and what the likely

       outcome was for people who were unfortunate enough to develop


                  Basically, this is an illness, as you may know, which tends

       to arise in adolescence or early adulthood, and it tends to run a

       recurrent course. It occurs. It may get better. But then it recurs,

       and then it gets better, and then it recurs again. It ultimately leaves
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       people in a state where they are disabled. They are persistently

       experiencing the symptoms of the illness, the hallucinations, the

       delusions, the impairment of their thinking, their interest in things.

       And it also erodes their ability to function, and perhaps most

       tragically, it changes the very sort of fabric of their being, of their

       personality, who they are. It leaves people, not in old age, but

       really in middle age, in a state of permanent disability, and often

       times requiring supervision, or in the case of these individuals, into


                  Fortunately, now we have treatments. However, the

       treatments aren’t always provided to people. They’re not always

       available, or people don’t necessarily know where to find them, or if

       they do, they don’t want to take them. And, the way we provide

       mental healthcare services allows for people to fall through the


                  A very good illustration of that kind of thing recently was in

       a major motion picture called The Soloist. How, how many people

       had occasion to see this movie, The Soloist? Right. So I usually

       sort of get no Hollywood’s case by saying they usually depict

       mental illness as psychotic killers, or in some sensationalistic way.
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       But this was really a very, I think, good effort to try and depict what

       can happen if treatment isn’t provided, or there aren’t services

       available for people with mental illness.

                  So this is about a young man, Nathaniel Ayers, who was

       born in Cleveland, was a gifted musician. He won a scholarship to

       Juilliard. He went to Juilliard College. Developed schizophrenia,

       developed his first psychotic episode. Didn’t get treatment. Or he

       got treatment but didn’t follow through on treatment. And followed

       a course which, unfortunately, befalls many people, where they

       sort of have their ups and downs. They don’t get sustained

       treatment. They don’t achieve recovery. They don’t sustain a

       trajectory of fulfilling their goals and potential. And he ended up

       homeless on the streets of Los Angeles.

                  There was a journalist who got to know him, just by

       coincidence, by chance, and tried to redirect him into what would

       be a more stable lifestyle, and engage him in treatment, but it was

       unsuccessful for two reasons. One, because Mr. Ayers, who was

       portrayed in the movie by Jamie Foxx, had no understanding of his

       illness, and did not think that he really was ill or needed treatment,

       even though he was suffering from the effects of it. And also, our
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       laws do not allow the imposition of treatment against one’s will,

       unless there’s manifest danger to other people or to self. So he

       was basically living out the rest of his days on the street. So it was

       a very good depiction of this failure of treatment.

                  Now, the difference between the first picture of Asylum

       Inmates and Nathaniel Ayers is that right now, we have treatments

       which absolutely work. They don’t work perfectly. They don’t cure

       people. They don’t work in everybody. They have side effects. But

       they definitely work, and we have a whole array of other types of

       services, from case management, supportive employment,

       psychoeducation, cognitive remediation, rehabilitation, which can

       really, really enable people to achieve high levels of recovery and

       go on to lead very fulfilling lives. But Mr. Ayers didn’t get any of


                  Now, if we look at what happened to him, in the course of

       what the natural history of schizophrenia is, it begins to sort of

       draw a picture that is going to really be the focus of my comments

       today, which is, given what our current state of the art is of

       treatment, what can we do to really cut the legs out from under this

       illness, stop it in its tracks, achieve the best level of recovery,
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       product the highest levels of remission?

                  This is just a schematic diagram of what the sort of

       general pattern of this illness looks like. So it really begins here at

       gestation, conception, because schizophrenia is known to have a

       genetic basis to it, which contributes to the vulnerability

       to developing the disorder by producing some abnormalities, some

       weaknesses in the way the brain develops. But this lies pretty

       much dormant until after puberty … childhood onset schizophrenia

       is very rare … and when people enter this period of adolescence,

       young adulthood.

                  People begin to get some kind of behavioral, some mental

       changes which are just loosely defined as prodromal signs,

       meaning, the kind of early warning indicators prior to having the

       diagnostic symptoms of the illness. The diagnostic symptoms of

       the illness occur, and people, when they seek treatment, get a

       diagnosis, they’re said to have their first episode of illness, their

       first psychotic break.

                  Treatment at this point, which is the first time it’s generally

       introduced, works. It works actually very well in terms of

       suppressing symptoms. But the majority of people don’t stay in
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       treatment. They don’t continue to take medicine. As a result, they

       have recurrences in the form of psychotic relapses. As they do,

       the phenomenon which leads people to the state that those asylum

       inmates were in, and the state that Nathaniel Ayers was in, occurs,

       this erosion of personality, of intellectual capacity, persistence of

       symptoms develop, all of which are kind of defined as


                  This deterioration is one which progresses downhill, not to

       the point like you see in other neurodegenerative diseases like

       Alzheimer’s disease, or Parkinson’s disease, where you die or you

       become totally bedridden, but to a point where people experience

       this kind of state where they’re chronically disabled and residually

       symptomatic. During this period, the symptoms of the illness which

       tend to worsen, and predominate are the negative symptoms,

       impairment in cognitive functions, and difficulty in being able to

       function in the world, in contrast to what occurs at the beginning of

       the illness, which is mainly the psychotic symptoms, the

       hallucinations, the delusions, the thought disorganization.

                  Now, for this reason, schizophrenia is a very costly

       disease. This is data from a study that was done by the World
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       Bank called the Global Burden of Disease Study. The evaluated

       what is the cost to society of all illnesses, heart disease, cancer,

       infectious disease, allergic disease, and various types of mental

       illnesses. If we look at the group between 15 and 44, arguably,

       one of the most important periods of life when people are coming

       into their prime, they can be most energetic and productive, four of

       the top ten are mental disorders. Depression was the leading one,

       and then alcohol/substance use disorder, and the third was


                  Now, why schizophrenia? Because of the fact that people

       get sick when they’re young. They never become full self sufficient.

       They go on to lead lives of disability, but they don’t die from the

       disease itself. So they live a long time, decades. And they require

       disability and support as well as services. So it’s a very expensive


                  Now, let’s contrast Nathaniel Ayers with this person. This

       is a picture of a good friend of mine named Elyn Saks. Elyn Saks

       recently wrote a book called The Center Cannot Hold. It’s about

       her story with schizophrenia. So she was a woman who was born

       in Florida. South Florida. She grew up in a nice family. Went to
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       college at Vanderbilt. And when she was in college, she began to

       get these prodromal symptoms of schizophrenia. She graduated,

       did very well, nevertheless. Went off to England with a Rhodes

       Scholarship. And while she was there, had a complete psychotic

       episode, was hospitalized there, treated, got better, came back to

       the United States, entered Yale Law School. Graduated. And now

       is on the faculty of the University of Southern California as an

       endowed professor, and just got a MacArthur Genius Award.

                  So what happened here? She, for whatever reasons, her

       own insight, her family’s guidance of her, the people that treated

       her when she got sick, first at Vanderbilt and then in England, and

       then at Yale, she got in treatment, she remained in treatment, and

       she had a high level of recovery, and she’s doing extremely well. Is

       she cured? No. Does she need treatment? Yes. Is she leading

       as product a life as she would have had she not had the illness?

       We don’t know really, but she’s leading a pretty darn good

       productive life now. So that’s what can happen. Now, the

       difference there is, she got sick. She had some exposure to illness,

       but it didn’t go on, and on, and on, and on, and recur and recur,

       and she didn’t fall through the cracks. And this was the outcome.
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                  So that’s kind of the point of this. The point of this is that,

       yeah, we’d like the new breakthrough which cures schizophrenia.

       We’d like the new medications which have no side effects. We’d

       like novel mechanisms. But given what we have now, what we

       know we can do, the whole trick is to prevent this. Of course, we

       need treatments for people here, and we need to keep trying.

                  That’s proven to be tough, and something that’s a little bit

       discouraging in that regard, that’s happened recently, is that in the

       context of this economic crisis, and with all of the criticism of the

       pharmaceutical industry, they’ve begun to retrench, and the

       retrenchment, unfortunately, has selectively led them to cut back

       on drug discovery, of brain drugs, and particularly in the area of

       mental disorders. So GSK, AstraZeneca, Pfizer, have just cut or

       eliminated altogether their drug discovery units in these areas, a

       very disturbing development. So we don’t know what the

       prospects of new, better things to come, in what time frame it is at

       this point.

                  But in the meantime, we are able to do things which

       interdict the illness, here. So, what happened to my movie?

       (Laughter) There we go. This is an animation of what happens to
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       the brain in the early phases of schizophrenia. So this is a

       combination, a composite of multiple subjects, who were studied

       with MRI, when they first got sick in their adolescence, and they

       had an MRI once a year for five years going forward.

                  What you see here is, they initially begin with their brain

       being mostly blue. This is not repeating. It’s supposed to be

       looping. Mostly blue. And it progressively develops more pink or

       red. That pink or red developing shows the loss of brain gray

       matter. This is what’s occurring during the illness when people are

       psychotic, when people have persistence of psychotic episodes,

       and when the psychotic episodes keep recurring, there is this

       persistent loss of very small amounts … it only amounts of one or

       two percent of brain gray matter.

                  (Background Conversation)

                  JEFFREY A. LIEBERMAN, M.D.: So what is causing this

       … is this. So this is a cartoon of the synapse, the connections

       between two cells that have their projections connect, as a

       synapse to communicate with each other. And these synapses,

       one neuron connects to the next neuron, via the secretion of a

       chemical called the neurotransmitter, to stimulate this neuron, and
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       propagate the nerve impulse.

                  When this process of chemical neurotransmission gets

       dysregulated as occurs in schizophrenia, this is the process which

       gives rise to the paranoia, to the hallucinations, to the false beliefs.

       Medication stabilizes that process and protects and stabilizes the

       synapse. However, if it goes on too long, if it occur repeatedly, the

       excess neurochemical is toxic to these cells, and it basically

       ablates or destroys the synapse.

                  Now, here you have a cartoon of cells in the cortex of the

       brain. This is the cell body. This is the different dendrites. Each of

       these little branches is at a point where connections are made to

       form synapses. These are called dendrites. These little

       projections from there are called dendritic spines. So this forms

       like a little arbor. When this occurs here, it doesn’t get treated, or it

       recurs repeatedly, it basically eliminates these little branches, so

       it’s like the arbor gets pruned. When it gets pruned, that’s what

       we’re measuring as this loss of brain gray matter. We can see it

       here. This is a postmortem specimen of somebody who had

       schizophrenia and died. This is a normal control. You see these

       little dendritic spines. There’s many of them on the dendrites. And
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       here, there’s very few of them, because they’ve been eliminated by

       this chemical toxicity that’s occurred.

                  So this an illustration of what the clinical consequence of

       that is. So these are people who were treated in their first episode

       of schizophrenia, and followed for a year. They’re all treated in the

       same way, with the same medication, same doses. And what you

       see is that there’s a high level of recovery. About 80 percent have

       a full symptomatic remission. But the degree and the likelihood of

       remitting is dependent on how long they were actively sick before

       they came in and they got that initial treatment.

                  The people that got treated faster had higher and faster

       rates of remission. The people that took longer to get treated had

       lower and slower rates of remission. So, indicating that this active

       phase is something we want to stop, or limit in the same way that

       when you have chest pain from a heart attack, or you begin to

       have symptoms of a stroke, seconds, and minutes and hours are

       important to get that treatment. In the case of schizophrenia, it’s

       days, weeks or months, but it’s still, the shorter, the faster the

       treatment, the better.

                  All this data has suggested, can treatment prevent the
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       progression and enable recovery from schizophrenia? The answer

       is, we certainly hope so. So these are data from a study of first

       episode patients, people in their twenties. They’re treated with two

       medications, haloperidol and olanzapine, and what you see is that

       pretty good level of recovery in terms of remission. A little bit better

       for this medication, olanzapine, but both treatments do very well

       because young patients respond to treatment. The key is get them

       treatment fast. And continue the treatment.

                  The interesting thing is, when we looked at the effect on

       brain gray matter of these different treatments, what we found was

       this. If we look at healthy volunteers, in their early twenties, we do

       an MRI on them, and we follow them for a year, and then do

       another MRI, we find that their total brain gray matter, at the first

       measurement, was 700 CCs. That’s about average for a young

       man. You don’t have age dependent decreases in gray matter like

       you have at my stage of life, when you’re passed 40, and you’re

       developing gray hair, and you’re losing gray matter as well.

                  People with schizophrenia had slightly smaller, in that first

       episode, about 15 CCs. So not a huge amount. But then over the

       course of that year, they lost about two percent. When we broke it
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       out into the different treatments, one of the treatments produced

       much less. Now, I don’t know that that’s due to the pharmacology

       of that drug as opposed to the fact that that drug may have been

       better tolerated, and people stayed on it more than they did the

       older medication, haloperidol, and that was the reason. But the

       point is that treatment was able to mitigate this loss of brain matter,

       which we think is the basis for the deterioration occurring in

       schizophrenia. This is a movie. See if you can activate that, the

       movie, which shows you the same thing.

                  (Background Conversation)

                  JEFFREY A. LIEBERMAN, M.D.: You see the red

       indicates that you’re losing gray matter. This is over the two year

       period of the study. And what you see is, there’s more red

       appearing in the hal group as opposed to the olanzapine group,

       which is showing the treatment effect. Now, these, in this study,

       the brain changes on MRI volume were associated with

       symptomatic and cognitive outcome, the less brain gray matter that

       was lost, the better the response of symptoms and cognitive

       function. So we think this is the real thing, and this is an important

       target for treatment.
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                  Based on this, we have this model that suggests that the

       genetic diathesis of schizophrenia involves producing

       abnormalities in brain development, which confer vulnerability to

       the illness. But this lies dormant until people in their adolescence,

       in their young adulthood, experience stress, and have a

       destabilization of these vulnerable neural circuits, which throws off

       the chemistry in their synapses, involving dopamine and glutamate.

       This produces the symptoms of the illness. Treatment here can

       stop this. But if treatment doesn’t occur, you get this chemical

       toxicity, and that leads to the degenerative process of loss of

       dendritic spines, cell processes, and then the deterioration

       associated with the illness.

                  Now, the goal, then, is to get to people and treat them,

       and keep them in treatment, early, and as long as you can. If you

       do that, you can prevent this from occurring. That basically is

       what’s happening now. So the NIMH has finally gotten religion.

       They finally have sort of appreciated this opportunity, and they

       funded a study called the RAISE Study. The federal government

       loves acronyms. So this is Recovery After an Initial Schizophrenic

       Episode project.
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                  Basically it says that rather than sort of save all of the

       psychosocial treatments and the sustained medication for people

       once they reach the chronic stage of the illness, put it all up front at

       the beginning. So it’s like closing the barn door after the horses

       have left. So now there’s a redirection of this total push, this

       intensive effort of treatment, the people at the beginning of the

       illness. This study has been funded. It’s ongoing in the United

       States currently. It’s targeted at first episode patients. So we’re

       looking at sort of the next generation of people. I think it

       represents real hope in terms of having a major impact on the


                  Now, because of the fact that we know getting to people

       early is beneficial in terms of producing better treatment outcomes

       and preventing the illness from getting any kind of foothold and

       progressing, and causing damage. People have said, aha, we

       know that people don’t develop schizophrenia over night. We

       know that it takes them some period of time to develop it, and they

       usually have these kind of early warning prodromal signs. So the

       focus has now become on this prodrome.

                  Here, what we see is that in this study that was done in
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       the United States, that if you look at people who have prodromal

       signs, you can find that if you follow them over the next year, to

       two, to three years, about 30 percent of them will go on to develop

       a schizophrenia-like psychotic episode, as opposed to their college

       or high school aged peers who will only have a one in 100 lifetime

       chance of doing so.

                  So this has been identified as a treatment opportunity,

       and there have been treatment studies which have attempted to

       look at, if we take people who have these prodromal symptoms,

       they don’t have a diagnosis yet, we’re not sure they have the

       illness, but we think they’re going to get it sometime in the next two

       to four years, and we treat them, can we prevent the onset of the


                  Now, the treatments that have been used initially for this

       were the actual treatments we use to treat the illness, the

       antipsychotic medications. Now, this may work, although the

       results are inconclusive, but it’s a little bit heavy handed,

       particularly given the fact that even though 30 percent of the

       people will go on to develop the full-blown diagnosis and psychotic

       episode, 70 percent don’t. So you’re going to treat them also? So
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       that’s been problematic.

                  More recently, there was a study that used, again, one of

       the fish oils, so omega-3 fatty acid. This just came out this year,

       produced a phenomenal result … if it’s true. And this was the

       result. So these are prodromal patients identified, all in their late

       teens, early twenties. This group was randomized to get omega-3

       fatty acid. This group got basically placebo. And you see that the

       conversion rate here in the placebo group was about 20 percent,

       and was close to zero.

                  Now, I’d love to believe that this is true, and we should

       use omega-3 for people who exhibit these signs or symptoms. I

       have to tell you that it’s a fantastic result. It was a good study. But

       until it’s replicated, we can’t take it to the bank. So this is very

       promising. But the overall strategy is one where we’re trying to

       basically treat people in this early phase of the illness.

                  I’m going to skip through my last series of slides, just in

       the interest of time, but let me just say one thing first. What we

       need in order to make this strategy a reality which is ready for

       prime time, is a diagnostic process which leads to a greater degree

       if certainty of the diagnosis. A 70 percent false positive rate is not
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       acceptable. In addition, we need to know what the best treatments

       for this prodromal phase are, and if it’s omega-3 fatty acid and fish

       oil, that’s great. But if not, we need to find out what it is, and it

       hopefully will be something other than the antipsychotic

       medications itself.

                  The way we’re going to do that is through imaging

       techniques, I think. These are the most promising, and we’ve

       identified an imaging technique which basically can identify who

       has schizophrenia, who doesn’t, and in the case of the prodromal

       symptoms, produces this marker which we think is sort of the first

       area of the brain that exists in the region of the hippocampus called

       the CA1 region, and the subiculum region, which is the first area

       that begins to go off when this chemical dysregulation begins. We

       think that by using this imaging technique, in prodromal patients,

       we can improve the diagnostic specificity from 30 percent to over

       80 percent. So that’s the hope.

                  I’m just going to blast through this and say that what

       we’ve learned is that schizophrenia is a progressive disorder. The

       disability is directly due to the gray matter volume loss. With

       antipsychotic medication and prophylaxis, we can prevent this.
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       And better yet, we can potentially identify people before they even

       have a full-blown psychosis if we get our diagnostic techniques

       refined and better. So from that standpoint, I’m very optimistic

       about our ability to treat patients in the future, while we’re awaiting

       newer and better drugs. So thank you for your attention. This is

       where I live.


                  JEFFREY A. LIEBERMAN, M.D.: Now, we’re going to

       take a few questions, and then I’m going to ask Benita Shobe to

       return to the podium to make some closing comments. We’ll start

       over here. Yes, Ma’am.

                  SHIRLEY ANN THOMSON: Shirley Ann Thomson(?). I

       work at the mental health center for … I’ve been 20 years, in

       human services, but I was a case manager, and the way I found to

       keep my schizophrenic clients from returning to the unit on a

       regular basis was to put them on medication IM, because very

       often they didn’t have a supportive family, and it they didn’t show

       up for their injections, I went and got them. And this kept many,

       many clients off of the unit. We just need more money for mental

       health, and the cuts. And I’m going to say one more thing, is that
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       the most important vitamin for a pregnant woman is to have a good

       husband. (Laughter) The father can be motherly. There’s no way

       the mother can be fatherly. We need the guys. Thanks a lot.

                  JEFFREY A. LIEBERMAN, M.D.: Amen. I agree.


                  JEFFREY A. LIEBERMAN, M.D.: Yes, Ma’am.

                  WOMAN: Yes. That’s definitely true. You need more

       support, not only the mother to support, but other people. That’s

       why I believe in having advocates, and siblings, if they’re there, to

       be there for the person. But I have a question. My son started

       when he was 12, and he started … or 10, or 12, and his first

       diagnosis was depression, school phobia … OCD … and then it

       went developing. So he went through all those. Fortunately, he

       doesn’t … the OCD, the germ phobia, and finally, hearing the

       voices. So I’ve worked with him a lot. He got over almost the

       OCD, because he had germ phobia. He would touch even the light

       switch. Then, now he hears voices. He’s on medication. He’s

       been through all the medications that you can imagine, that I can

       mention to you. Zyprexa was one of the last, Seroquel, then

       Abilify, and he started with risperdal. Now, we tried all of them to
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       see which one would work better. So far he’s on Abilify 30

       milligrams …

                  JEFFREY A. LIEBERMAN, M.D.: Ma’am, what’s the


                  WOMAN: The question is, the voices. When do you start

       medicating a person who is diagnosed with schizophrenia is when

       they say I hear voices, is that when? Is that enough? Or is …

                  JEFFREY A. LIEBERMAN, M.D.: if somebody is having

       hallucinations …

                  WOMAN: Yes. Yes.

                  JEFFREY A. LIEBERMAN, M.D.: Depending on the

       nature of those hallucinations, that probably by itself would be

       enough to warrant medication.

                  WOMAN: Yes. Yes. Now, what if the hallucinations,

       even with medication, do not go completely away? Of we said it’s

       not curable yet, or, hopefully.

                  JEFFREY A. LIEBERMAN, M.D.: Then you need to

       adjust the dosage. Or consider switching to another medication.

                  WOMAN: All right. Is Abilify an antipsychotic?

                  JEFFREY A. LIEBERMAN, M.D.: Yes, it is. Yes, it is. It’s
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       a new type of antipsychotic with a different kind of pharmacology.

                  WOMAN: Yes. Now, there are different types of

       depression. For example, clonazepam helps a lot…

                  JEFFREY A. LIEBERMAN, M.D.: It does.

                  WOMAN: … to calm him down when he has the


                  JEFFREY A. LIEBERMAN, M.D.: Why don’t we talk

       about this individually, because …

                  WOMAN: Yes, I would like to see if we could do that,


                  JEFFREY A. LIEBERMAN, M.D.: Yes. Thank you.


                  WOMAN: Yes. I have a sort of individual question, but

       people might be interested. Are you the doctor Lieberman that

       developed the social skills training in California?

                  JEFFREY A. LIEBERMAN, M.D.: No, that’s Dr.

       Liberman. L-I-B-E-R-M-A-N. We came from the same stadl(?) in

       Russia, but … (Laughter) at Ellis Island they dropped his E, and he

       got routed to California and I got routed to New York.

                  WOMAN: Yeah, because you were in California. Can
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       you speak …

                  JEFFREY A. LIEBERMAN, M.D.: He’s the psychosocial

       guy. I’m the pharmacology guy.

                  WOMAN: I see. I thought maybe you transferred over.

       (Laughter) But would you speak a little bit to the social skills that

       maybe that could be a behavioral treatment? It’s not done nearly


                  JEFFREY A. LIEBERMAN, M.D.: Absolutely. And the

       question before, for Dr. Volkmar about the overlap between autism

       symptoms and schizophrenia, I think is very relevant for that.

       Social skills training and rehabilitation such at that, that Dr. Robert

       Liberman developed were very rigorously developed. It’s turned

       out, if you use those, that people, when they’re in the late stages of

       the illness, the chronic residual phase of the illness, very labor

       intensive. Very expensive in terms of personnel. And the effect,

       even though it does product a beneficial effect, is limited.

                  On the other hand, if you use similar types of techniques

       early in the course of illness, they can produce much bigger

       effects, and the level of expense and intensity of treatment is much

       less. So I think in terms of being … it’s like rehab after stroke. It’s
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       very hard if people have had a severe stroke, and you’re getting

       them late, whereas if you use it early, it can be very effective. So

       it’s definitely part of an optimal form of treatment. Yes, Ma’am.

                  WOMAN: Thank you. Is schizophrenia a result of an

       inefficiency to metabolize omega-3s? How much do we need as a

       preventative measure? And does it help after the first break?

                  JEFFREY A. LIEBERMAN, M.D.: There has been a

       theory, an old theory about lipids and a faulty lipid metabolism

       being a causal mechanism of schizophrenia. It’s only been a

       theory. He evidence supporting it has been vey sketchy. So it’s

       really not something that treatment development has focused on.

       If this omega-3 finding can be replicated, I think this will really inject

       a lot of interest in developing treatments to try to focus on this

       theory. So at this point, I think we have to wait till the replication.

       In the meantime, taking fish oil is not bad anyway. It’s useful for

       cardiovascular purposes. It’s useful in terms of aging and

       intellectual function.

                  WOMAN: How much was seen to help? Do you


                  JEFFREY A. LIEBERMAN, M.D.: What was the dose?
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                  WOMAN: Yes.

                  JEFFREY A. LIEBERMAN, M.D.: I don’t recall the dose,

       but the article is available if you Google omega-3, prodromal

       psychosis, it’ll come up and it’ll describe the dose. Yes, Ma’am.

                  WOMAN: Yes. Are there any really early indications that

       people could use to predict the potential for having a psychotic

       break or developing schizophrenia?

                  JEFFREY A. LIEBERMAN, M.D.: Family history is the

       strongest indicator.

                  WOMAN: Family history?

                  JEFFREY A. LIEBERMAN, M.D.: Yes. Other indicators

       for early in life have to do with children exhibiting some kind of

       social disability, delays in motor development, attentional

       disturbances. The problem is, sometimes when they develop

       attentional disturbances, that leads them to be treated with

       stimulants, and the stimulants in turn don’t necessary alleviate the

       attentional problems because they’re not coming from ADHD, and

       they serve to help to provoke the psychotic symptoms or the

       disorder. There are nonspecific kind of precursors, or signals, for

       increased risk for schizophrenia, but the single biggest one is
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       family history.

                  WOMAN: Thank you.

                  JEFFREY A. LIEBERMAN, M.D.: Yes. Yes, Ma’am.

                  WOMAN: To follow up on that, two generations of

       schizophrenia known, any new studies, any … I understand what

       you just said, but anything that you can do for the next generation,

       to watch it, monitor it … study it?

                  JEFFREY A. LIEBERMAN, M.D.: If people have a high

       index of suspicion of schizophrenia in a child, right now, the thing

       to do is really to seek psychiatric consultation, monitor the

       development of the child, still be very conservative about treating,

       unless there’s a clear indication of symptoms of another disorder to

       treat. And then, when there are the emergence of prodromal

       signs, or signs that look like they’re verging on psychotic signs,

       then introduce treatment as quickly as possible.

                  Very soon, I think we’ll have some diagnostic tests which

       will aid in enhancing our level of certainty, like the imaging test.

       Also, we will have genotyping, because we have a number of risk

       genes that are shown to be associated with the illness. We’re right

       on the cusp of when those are going to be ready to be used
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       clinically. It’s probably within the next five years, I would say, and

       that will also aid to be able to assess these people who we have a

       higher index of suspicion about, or are at higher risk. Yes, Ma’am.

                  WOMAN: Hi. One of the symptoms is to actually hear

       voices and see things that aren’t necessarily there. That

       sometimes is mistaken in religious sectors and seen as something

       spiritual. I’d like to know if you can address, or if you know of a

       study that correlates spirituality, religion, and schizophrenia. Thank


                  JEFFREY A. LIEBERMAN, M.D.: Yes, I think that’s a

       very important point. Just having hallucinations does not

       necessarily mean this is psychosis or a disorder. There are certain

       religious, cultural factors, or just a sort extraordinary mental states

       that people induce or experience that are not necessarily due to a

       disorder or indicate treatment. So it’s important that this

       phenomenon, this hallucination, or this behavior be evaluated, first,

       what is the content of the behavior? Is it consistent with the

       person’s experience, or is it completely bizarre and inconsistent?

       Secondly, is it distressing? Or painful to them in some way?

                  If it’s experience in the context of something which is part
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       of the person’s religious observance, or cultural orientation, it’s not

       causing them to stress, then there’s no reason a priori just by itself

       to regard it as pathologic and needing treatment. We’ll take two

       more questions, and then we’re going to have to stop. Did you just

       ask a question?

                  WOMAN: No.           That was the last time. Last speaker.

       Okay. On medication, I’m sure everybody knows, and everybody

       has problems keeping people with psychiatric disorders on

       medication, and we know that you should, but is there any

       evidence that shows someone with schizophrenia that hasn’t had,

       let’s say, positive symptoms in X number of years, can try to go off

       the medication? And in conjunction with that, can MRIs with

       someone who is in their twenties or thirties, and has schizophrenia,

       can the MRIs help at this point on how much medication, or is it

       just theory for the future?

                  JEFFREY A. LIEBERMAN, M.D.: If you have a well

       diagnosed, bona fide schizophrenia, the likelihood of you being

       able to survive for long periods of time off medication are low. But

       if you want to take the chance, you can taper off it, but remain in

       treatment and be very vigilant to any signs of recurrence and be
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       prepared to resume treatment in that event. It’s a little risky, but it’s

       feasible. The likelihood of it working, I think, indefinitely is very low.

                  In terms of being able to dose medication based on MRI,

       not really. There’s another method, though, PET scanning. PET

       scanning is a way where you can calibrate dosing of treatments,

       and involves doing a measure of receptor occupancy in the brain.

       So that’s something which isn’t done as a standard clinical

       procedure, but it is very effective as a research procedure.

                  WOMAN: So you couldn’t do that with someone that was

       being treated for schizophrenia, or could a psychiatrist order that?

                  JEFFREY A. LIEBERMAN, M.D.: You could. You’d have

       to refer them to a research center where they were doing that kind

       of PET scanning.

                  WOMAN: Thank you.

                  JEFFREY A. LIEBERMAN, M.D.: Last question, yes.

                  WOMAN: I guess my question kind of goes to the

       medical side of the diagnosis, which is, how important is it to get

       one of these PET scans, or imaging scans in order to make a

       diagnosis? Should a diagnosis be made without that kind of test?

       And then my second question is, in regards to the doctor, Elyn
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       Saks, in terms of someone who is schizophrenic, and you see that

       they have potential, how important is it to evaluate decisions of

       challenging them, and meeting potential, as opposed to the risk of

       stress in conjunction with a reoccurrence of the illness?

                  JEFFREY A. LIEBERMAN, M.D.: I lost track of your first


                  WOMAN: (Inaudible Portion)

                  JEFFREY A. LIEBERMAN, M.D.: The imaging?

                  WOMAN: (Inaudible Portion)

                  JEFFREY A. LIEBERMAN, M.D.: For diagnosis. That’s

       right. So this is a dilemma, because the insurance companies

       won’t pay for it routinely now. It’s my feeling that every first

       episode patient should have an MRI, not necessarily a PET scan,

       but an MRI, to evaluate brain structure, both in terms of some other

       cause that could be mimicking schizophrenia, or to evaluate brain

       changes that are consistent with a diagnosis of schizophrenia. So

       you can frequently figure out a way to get it as part of the

       diagnostic workup without saying you’re doing it for the purposes of

       diagnosing schizophrenia. So I think it’s definitely desirable to do.

       In the very near future, I think we’ll probably be doing more than
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       just MRIs, because the PET scans technique is are very useful,

       and really being able to diagnose psychosis, the actual psychotic

       process itself.

                  In terms of Elyn Saks and stress, that’s a very good

       question. So stress is … nobody wants stress. But as Dr. Krystal

       showed, it’s not as bad for everybody as it is for some people. In

       the case of people with schizophrenia, it’s potentially very bad.

       They’re more vulnerable to it. So on one hand, you don’t want to

       really limit people and undershoot what they’re able to do. On the

       other hand, you don’t to put them into something that’s overly

       challenging. So I would say here, you err on the side of caution.

                  You may not be trying to get back on track to win a Nobel

       Prize, or become the CEO of a Fortune 500 company, but you

       should certainly try and set goals and don’t figure you’ve got to

       lower your sites because of some lifelong disability. But you don’t

       necessary want to push them. One of the biggest mistakes that’s

       made, I think, with first episode patients, is they’re usually in

       college. They take a semester. Or they get sick. They go into

       treatment. They want to get back so they don’t lose a semester,

       lose the year. That’s not a good idea. It’s much better to take your
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       time, be fully stabilized, get reacclimated, more gradually. Then

       avoid the stress that can produce the relapse.

                   I just want to say that you have been an absolutely

       fabulous audience, and ask great questions, and its’ been just a

       sheer pleasure for all of us that are involved in this. I hate to call

       something to an end, but I think we’ve gone on for a fair amount of

       time today, so let me ask Benita Shobe to comet to the podium to

       make some closing remarks, and then we’ll adjourn this session

       until the next time we have a chance to meet.


                   BENITA SHOBE: Well, clearly, the first thing we want to

       do is thank our presenters, Dr. Lieberman, and your excellent work

       as our facilitator. Dr. Krystal has left. Dr. Wisner is still here. And

       Dr. Volkmar, I think he has left as well. But thank you so much. So

       they’re still around for just a little bit longer. Let’s thank them,



                   BENITA SHOBE: So why does NARSAD do this?

       Clearly, empowering our constituents with more knowledge, more

       knowledge. I had an old trainer one time telling me that repetition
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       is the god of knowledge. So seven years, and quite probably eight,

       because the more we hear, the more we learn, the more

       empowered we are as consumers. It’s not uncommon to hear the

       term ivory tower associated with academic institutions, and with

       scientists, and our goal in doing this is to … let’s reduce that gap.

       Let’s make sure that our scientists who are working on your behalf

       have a chance to interact with you, and you have a chance to

       interact with our scientists, so we are bringing that ivory tower to

       our families as a result of your extraordinary interest.

                  We also want to do things like this to gain some publicity,

       to gain some awareness, to help reduce the stigmas that are

       associated with mental health or mental illnesses. Of course, we

       also want you to take time, everybody got an evaluation? We

       need to know the effectiveness of what we do. We need your

       candid feedback. We need to know what direction to take. On

       Monday, we’ll start talking about what we want to do. In fact, we’ve

       been talking about it a little bit already, what we want to do next

       year. Your input is sincerely valued, and we will be looking at

       absolutely everything that you recommend, and determining

       whether or not we’re able to deliver.
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                  Of course, the last thing that I would like to share is that

       our goal, obviously, is to accelerate our capacity to deliver

       information and education services such as this, but more

       importantly, to continue to fund, and fund at higher levels, at

       increased levels, our scientists, so that we can impact that road to

       discovery and recovery much more quickly. So there is an

       envelope. So here’s that pitch. There is an envelope in your

       program. We’d like you to consider making a gift to NARSAD.

                  We are blessed with very, very generous support of two

       families that underwrite all administrative cost … all administrative

       cost. But the cost of our research is extraordinarily high. It’s getting

       higher and higher. We have not, in the 20 plus years, 27 years, I

       believe, of existence, been able to increase the amounts that we

       give to our young investigators, and everything has gone up

       exponentially in cost. So we are working on a campaign.

                  We are launching a campaign, for the next decade of

       brain and behavior research, and our goal is to accelerate the

       activities that our phenomenal scientists … aren’t they smart?

       They’re brilliant … that our phenomenal scientists deliver, and

       certainly look more and more forward to treatments, and
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       eventually, cures. So please take the time to read your materials.

       Absolutely, the evaluation is critical. And to the greatest extent that

       you are able to do so, we would appreciate your considering a

       donation. And greater involvement with NARSAD. Indicate that on

       our evaluation, and we’ll be in touch. Thank you.


                                  (END OF TAPE)

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