>> welcome to our program. tonight a special edition of the charlie rose b brain series year two. and our fifth episode we focused on schizophrenia. >> we're going speak about the most devastating of all psychiatric illnesses, schizophrenia. but now as you learn we are really beginning to understand the beginnings of a scientific bases of schizophrenia. we have danny hurley here who can tell us what it is like to actually experience the disease. >> rose: episode 5 of the charlie rose brain series 2, underwritten by the siemons foundation. coming up, about the most exciting scientific journey of our time. >> understanding the brain. the series is made possible by a grant from the siemons foundation. their mission is to advance the frontiers of research in

the basic sciences and mathematics. >> funding for charlie rose was provided by the following:

captioning sponsored by rose communications from our studios in new york city, this is charlie rose. >> tonight we continue our study of the human brain, examining one of its most devastating diseases, schizophrenia. schizophrenia is a complex mental disorder marked by disturbances of perception, cognition, emotions and motor behaviors. its symptoms vary from delusions and hallucinations to disorganized thoughts or behavior. despite years of intense study of the origins and development of schizophrenia remains a mystery. we cannot recognize it in physical features of the brain in the same way, for example we know plaques and tangles that show alzheimer. we also don't know exactly what causes it. though it's believed to be a

combination of genetic and environmental factors. what is certain is that is the disee-- diseases devastating affects, it's estimated 1% of america suffers from schizophrenia, usually in late adolescent or early adulthood without regard to class, race, gender or culture. everyone from jack kerouac to brian wilson and john nash have fought the disease of schizophrenia, yet the lack of understanding about it has lead many to hide their diagnosis. more recently though some patients have begun to speak publicly about their experiences. danny hurley is one of them. he was diagnosed with schizophrenia while a student at georgia tech. he joins me this evening to share his story and his insights on the disease. also joining me tonight a remarkable group of scientists steven paul is director of the alz alzheimer disease research institute and a professor the cornell medical college. cornelia bargmann is a professor at rockefeller

university, judith rapoport is chief of the child psychiatry branch at the national institute of mental health. david lewis is a professor of translational neuroscience and chairman of the department of psychiatry at the unirsity of pittsburgh and once again my esteemed cohost is dr. eric kandel, a nobel laureate, professor at columbia and a howard hughes medical investigator. >> so tell me where we are today. what are we going to find out on this journey. >> we are going to speak about psychiatric illnesses today. in the last few programs we spoke about neurological illnesses, disorders of consciousness, of cognition. today we'll speak about psychiatric illnesses and the most devastating of all psychiatric illnesses, schizophrenia. we have danny hurley here who can tell us what it is like to actually experience the disease. the disease is tragic from several points of view. first of all it's fairly common. 1% of the population worldwide suffers from schizophrenia. two, the disease affects people early in their lives. and often is not remitting.

so it's with them for the rest of their life so it really affects people in a very dramatic way. we have known about schizophrenia for a very long time. but we've had very little scientific understanding of it. so hip october rattees already spoke about psychotic illnesses. but it wasn't really until the beginning of the 20th century that we began to make sense out of it. people didn't know how many difern psychiatric illnesses were there. where all psychotic illnesses, subcategories of one or were there many different once. and a mill, our first hero was the one who began to put psychiatry in a scientific basis. he said we must make diagnosis like they make in other areas of medicine. in the absence of biological markers you can use aspects of the clinical history to help. you can see what are the nature of the symptoms the disease has. what is the course of the disease over time, and

what's the final outcome. and when he looked at sky cot-- sigh scottic illnesses, he found he could divide them into two major groups. disorders of thought and disorders of mood. he called disorders of thought dementia precox. and he called it precox, that is dementia early in life because he said it's very different than senile demeant back, aldz alz disease because this starts much earlier but it's similar to alzheimer disease in the sense that the cognitive symptoms are the prominent features of the disease and they carry throughout the life of the patient and it's nonremitting. he called disorders of mood manic-depressive disorders. and he saw them as very different. the major symptoms were feeling terrifically good, hypereuphoric or feeling sad. that unlike schizophrenia there were remissions in

which people really functioned quite well. and often although not invariably the outcome was good. the distinction between these two major psychotic disorders although there is overlap has carried forth to this day. we still practice-- psychiatry so, he is the scientific founder of the field. however a number of people, particularly u glean bloyler objected to the conception of dementia precox. and they objected for many reasons. one is they thought that dementia was only one component of the disease. he was not exclusively a cognitive deficit, number one. number two, he said he saw patients who developed the disease later in life, not necessarily early. and he saw a number of patients who did well with the disease after many years. and danny is a perfect example of this. and he called the disease

schizophrenia. he saw it as a splitting of the mind, as a splitting off of the feeling aspect from the cognitive aspect, from the motivational aspect of the disease. and this has become really very fundamental to understanding of the disease an most of it except that definition of the disease, as the one we work with. tragically although we began to understand the disease, there was really no effective chemical treatment. and then a fascinating story developed. paul chap entier a french chemist began to develop an anti-histaminc compound that turned out to be use in the treatment of schizophrenia and this is a complete accident. and a number of drugs that were developed in the early phases of developing a psych pharmacology treatment came out serendipitously. the company he worked for was the first company to discover anti-histaminics

and realizing these are good for allergic diseases. but the trouble with the early ones they developed is they had a lot of side effects. so they asked company to develop better ones with fewer side effects. and he came up with a drug called thorazine that had fewer side effects. and as it went into criminal call trials people were amazed at how calm the patients were. they were much more relaxed than they had been before. and the two french psychiatrists noticed that if psychotic patients, specifically schizophrenia patients took it was like a magic bullet. they stopped hallucinating and having delusions t made a fantastic impact. it came to the u.s. in a short period of time. the fda a of proed it. and by 18954. >> this is one of the reasons why so many at the

state hospitals were emptied out. now in the early days, we really didn't have a scientific understanding of the nature of schizophrenia. and so these first drugs were not only developed serendipitously but the second generation was based upon trying to improve what was the first generation it was really empirical instead of having a profound understanding of the disease. but now as you learn, we are really beginning to understand the beginnings of a scientific basis of schizophrenia. and therefore the hope is we'll develop a whole new range of drugs that are based on the mechanism of the disease rather than imitation of the previous generation of drugs. so we are going to learn a lot about why psychiatry is and where it's going as a result of this discussion today. >> rose: so we should begin with steven paul and give us a clinical description of what we are talking about. >> thank you. patients with schizophrenia have a variety of symptoms during the course of their

illness. we have generally subdividing these into three categories or three clusters or dimeant-- dimensions of symptoms. the positive symptoms, negative symptoms and cognitive symptoms. the positive symptoms of schizophrenia are often the very first symptoms that patients experience when they first become ill. and these are often is very frightening to patients and their families. patients can become quite agitated as a result of these symptoms. and they fall into various different categories themselves. so positive symptoms include first and foremost hallucinations. these can be visual in nature. but often they're auditory. patients who have schizophrenia hear voices when they're not there. and these voices are often very critical and abusive at times. they can even cause patients to do some harm to themselves or others. they're very troubling symptoms, you know, for

patients with schizophrenia but very common, very common. now positive symptoms also include delusionsment these are false beliefs. beliefs the patient has when there's actually no real evidence that such a belief is real. and these often fall into different categories. the most common here again are paranoid delusions. patients with schizophrenia often feel as others are out to get them or following them or trying to do bad things to them. a not uncommon paranoid delusion is that people are trying to poison them. particularly with their medicine. so that's a very difficult, very challenging type of thing to feel when you're a patient with schizophrenia. other common delusions that are experienced by schizophrenics, we call these delusions of reference or control. patients often feel that they're getting special messages just for them from the television set or the radio.

often feel that people can control their minds. so that's a very common set of delusions that are part and parcel to these positive symptoms. delusions of grandeur. patients with schizophrenia often feel they is have special powers. so forth nationally as eric mentioned, most of the drugs that we have today for many patients if not most patients will effectively reduce these symptoms to a great extent. but i think it's important to point out that only about 20% of patients have full remissions. they become completely asymptomatic with medications or other treatments. and about a third of patients don't seem to respond very well at all to the meds. now unfortunately, there are these other symptoms. the negative symptoms it of schizophrenia and the cognitive symptoms. and these are the most pernicious and difficult symptoms to treat. its medicines don't work very well at all for these symptoms. so negative symptoms refer

to the absence of normal behaviors that most normal people, healthy people experience. a lack of energy, app pathy-- apathy, lack of motivation, patients with schizophrenia sometimes don't have ambition or drive. and this can, unfortunately, be misconstrued as laziness when in fact it's really part and parcel to the core sim to mattology of the disease -- sim-- very difficult symptoms to treat. and finally we have the cognitive symptoms of the disorder. the dementia. and patients with schizophrenia have inabilities sometime to gather their thoughts, to follow a train of thought. they also have memory impairment. if we give them a memory test they tend to be impaired in that way. and particularly a type of memory called working memory is a problem for them. in addition, they're

impaired with what we call executive function so they're unable to do the every day sorts of things that we need to do to be effective in our daily life or at work, et cetera. and therefore very difficult for many patients with schizophrenia to be gainfully employed. often difficult for them to mary-- marry and have families. so the cognitive symptoms and negative symptoms are really often the most troubling. and ones that we, right now, don't have terribly effective treatments for. >> rose: introduce to us danny. >> so danny, welcome. and thank you for being with us. >> thank you for having me. >> we have danny hurley who is a person who has experienced schizophrenia firsthand. and so danny, i thought we'd start by having you tell us a bit about how you were doing before you became ill with schizophrenia. what happened when you became ill and tell us a little bit about how things have been going ever since. >> well, before the onset of the disease i had almost unlimited potential.

i was the valedictorian of my high school class. i was a national merit scholar, and i took 10 advanced placement courses and i scored in the top 5% of nine of them is so i could have went to any school in the country. >> what happened to the 10th. >> actually, i wrote about the wrong subject on an essay. i could have went anywhere in the country but i diseeded to go to georgia tech. in my first year there i got a 4.0 grand point average. after that i went on a trip to europe. and i started writing a journal about my days in europe and i was having the time of my life. and the thoughts in the journal slowly became very paranoid. i started writing about things like string theory. i wrote about things like networks and waves. and i started writing in

secret codes so nobody else could steal my ideas. after a day of writing i slip mood full psychosis and i had to be returned to america. while i was on the plane back to america, i thought i saw the devil three times. and i thought i was being sent to a parallel universe where dinosaurs existed. i spent ten days in a psychiatric hospital getting back from psychosis to reality. and after being in the hospital, i spent four months at home. and i would describe it as mild cat tonya, in addition to blunted emotions. and my psychiatrist decided to do something drastic so he put me on the anti-psychotic clozapine and

the difference was like night and day. and i was able to return to georgia tech. i-- i graduated with highest honors. and i decided to go to grad school and focus on neuroscience. and i did well in classes but in research i just could not focus on the task at hand. so so i was able, though to write a masters thesis on connectivity in the brain. and to this day i think that that masters thesis contains the meaning of life. and for that reason i have a saviour complex. and basically i feel that the entire weight of the world is on my shoulders. i decided to try to make the masters thesis to a dissertation so i went to the university of pittsburgh to are be in the center of

cognition. i took a class in psychology and sat in the back of the class and could understand nothing from that class. so i had to leave the ph.d program in dis-- disgrace. when i left at that point, nobody would hire a graduate school dropout so i had to spent a year at sears telling tvs. i have gone between unemployment and contracting jobs and i suffer from anxiety, depression. i have suicidal thoughts. and-- it's tough but -- >> despite that you are able to have a meaningful relationship with a wife. >> i have a wife, monica and i love her very much. i have a job doing work in

medical coding and i'm able to multitask and do pretty well. so i do have a lot of thing goesing for me in my life. >> danny, tell us a little bit of those first symptoms. those were obviously very frightening to you and your parents when you first got ill. tell us a little bit more about what those were like and then have you had any more of those, those positive sim 2078s since you first became ill. >> well, i mentioned my devices of grandeur, that is the main source of my positive symptoms. the negative symptoms are what holds me back. you mentioned executive functioning. and i am unable to manage the course of my day very well. i spend about six hours a day watching tv because it calms me. but i do have a very good life. i think the clozapine is

responding very well. so. >> so it has really helped you. >> yes, but i think as dr. kandel mentioned, that there are better medicines that can be developed. and in order to do that we have to find a cure, well, find out what the point of the disease is, we have to find a cure and to do that we're going to need more funding in schizophrenia research. >> did you know what was happening to you? >> yes. i accepted it when i returned from europe to the psychiatric hospital. i accepted what was happening. >> they told you the diagnosis and you accepted it. >> yes. and there is a great stigma associated with-- with schizophrenia so it's hard to-- not being able to tell friends and family about

what's going on. >> characterize the stigma as you see it. >> well, i told my friend that i was going to be on the charlie rose show. and they asked why and i couldn't tell them i would like to be able to hold a conversation with somebody and have them realize that it's a neurological disease. aferbth and not something that makes me crazy. >> it's a brain disorder. >> definitely. >> this is amazing. >> it really is. >> the stigma is still associated with the disease. everyone foes this is i a disease of brain. this is not bad behavior on your part. >> right. >> and was's the hope of drugs here? >> well, we hope to get better drugs now. danny is on a rather special medicine. it was actually discovered in the '70s and reintroduced in the u.s. in the 80s.

it's called clozapine. it's something we call an a trip -- atypical anti-psychotic in contrast to that first generation. >> the drugs that first came along were effective for the craziness, the positive symptoms but had very bad side effects. it looked like parkinsonian side effects. so people began to get some insight on how they worked. they worked through the dopaminitric system and blocked certain reseptemberers. we'll discuss this later on. so using that idea, people tried to develop drugs that don't have those side effects if. and that's what's called the second generation of anti-psychotics. >> let's turn to the genetics. understanding the genetic basis for schizophrenia. >> well, the first thing to say about that is that the highest risk you would ever have of developing schizophrenia is if you had an identical twin with schizophrenia. then you would have about a 50% chance of developing

that disorder in your life. and as's true even if you are not raised in the same family. even if they are adopted twins raised separately it tells you there is some sort of a genetic risk, much higher than the risk to the population, about 1%. if also tells you those genes can't be acting alone because it is not 1 --% either there are interactions between genetic risks and the environmentment a big piece of progress has happened in schizophrenia in just the past few years has been understanding something about what that genetic risk is. at the granular level. what kinds of molecules, what kinds of brain function are different in patients with schizophrenia and unaffected people. and this has been a huge project that's involved hundreds and thousands of scien trust-- scientists and thousands and tens of thousands of schizophrenics and their families. it's a huge collaboration, really, to get that information. and from that we have started to tease apart some of the threads of what's

happening. so here's one thread that comes out of the genetics. schizophrenia, typically, people start to show symptoms as danny did in their late teens in college. but when we look at the genes, we find that many of them are acting in, before birth while you're still in the womb to set up the development of the brain. so the risk is some sort of a vulnerability that set up very, very early that makes the brain show problems much, much later. and that same idea comes up from our understanding of environmental risks tooment one of the most well understood environmental risks for schizophrenia was made based on its discovery after world war ii, after the dutch hunger winter, that children who were born after that winter, 18 years later had a much higher spike of rates of schizophrenia. something about being starved in the womb had created a risk for them so we're learning that we have to think about very early

development, not just about what happened when you are an adolescent or teenager or freshman in college. and then we're learning some over things too. there's something about inflammation of the immune system and disease that's important. there's something about certain kinds of electrical excite ability what are called calcium channels that sort of convert short term information into slightly longer-term information that's important. and finally there's something that's a big surprise about just diagnosis which is that in diagnosis there are sort of lumpers and splitters saying all these people are the same. we will lump everybody together and say this is schizophrenia. or you can split out different groups. and what we've discovered from the genetic point of view is that neither lumping nor splitting has been-- has been the right description. there seem to be many different kinds of genes that can create this vulnerability to schizophrenia. and usually probably several are working together in one person.

and conversely, some of the same genes that create a risk for schizophrenia can create a risk for by polar disease. and another group of the jeans that create a risk for schizophrenia can create a risk for autism so here we have these different diagnoses early diagnosis of autism, adolescent schizophrenia, different mood disorder, by polar disease but some of the genes are overlapping. and so we really need to puzzle that apart to reach the next stage of understanding. >> there is really quite fascinating because the term autism comes from bloyler and he described it as negative symptoms, lack of social interaction, so he had some insight, even though one didn't think of autism as a disease, it emerged in the 1940s, he already had some insight that this was an aspect of character that can be differentialally affected. and cory's point is a very modern point. we thought for a while that these very much at kreplen

said were quite discreet entities and to some degree they are, but there is an overlap in the midle that is important to realize. the other things that makes the genetics so hard it is it is not like early onset alzheimer disease in which you have one genetic defect that causes a whole disease. you have a lot of genes acting together each having a small effect, producing the syndrome. >> rose: juddist tell us what we have learned from early onset alzheimer. >> this approach of taking in this case children before they're 13 who develop schizophrenia is an approach that has very much paid off across all of medicine if you think of early onset alzheimer or breast cancer, for example. first of all, in their early development, when they were two, three and four, a third of this group of children that we have studied were actually seen for what looked like autism-like problems. -- as was making a connection we did not connect at all. thoughs tended to improve

and then there were a knew years that were okay and then schizophrenia began. they also had other problems such as learning problems, and language problems. suggesting a kind of red flag on the brain developmental milestones of a not very specific sort but higher in this group in their early years than in general in general. and a couple of biological markers have kind of leapt out at us over the years. one is that they have a higher rate not just in the general public but a higher rate than latter onset schizophrenia of genetic abnormallallities, species pieces of duplications or deletions too small to see with a microscope called copy number variance and just plane chrome someal abnormallallities, missing copsees, or a risk factor even in adult patients but it's more so in this group. and perhaps most interesting of all, we have been able to study brain development at a

much yinger age in people with schizophrenia because we were recruiting children and their siblings. and there are a few videos that go with this. and the first makes the point which is a film made of brain development between conception and birth. and the point is how much of brain development takes place before you're born. these are only pictures of the cover text or outer layer of the brain, of course. but inside you can also show with different ways of looking at these that all the white matter tracks are basically laid down by the time you're born too. so that the risk such as for infection or famine as corey talked about can have very major affects on early brain development long before the later period. now what we have been studying is the development of the children in the childhood onset schizophrenia group, most of

whom are above age 7. but the next video is something we call a subtraction movie. and this is thinning of the brain which is a normal process but where you see this film in red, is where the patient's with, who have schizophrenia are way ahead of the healthy controlled. and the process is a pruning of synapses that occurs during these years. and it looks as if they're going too fast. there's something regulating it that it's happening too fast. and what you see at the end of this movie is two areas of thinning by is what you see in a typical adult patient. that's what is left is still a bit thin. and finally and to us perhaps the most interesting is we also study brain development and made these ten year movies. it doesn't seem fair. you can see them in 30 second wlens it takes ten years to make it. but the next video shows which is of the healthy

siblings, and what that shows is that early in life the healthy siblings have only a small amount of thinning. but by the time they're in mid address ents it has disappeared completely and the point thereof is that these siblings is have a resilient brain. in some ways it gets better. and that may be a very interesting what the scientists call pheno type or pattern of brain development to study to see what they do to so to speak slug it off. and that may be one of the most interesting leads we've had it also suggests there may be special periods for intervention but we'll get to that later. >> judy's strategy is really a wonderful one because what off sen we learn with alzheimer, learns a great deal by early onset disease so to take advantage of the early onset schizophrenia is a very powerful strategy because we see how many things can go wrong in early brain development of which

schizophrenia is one. and from david's work, we understand what's happening inside the brain to account for that. >> this is a physiology of looking at the biological mechanisms. >> yes, charlie. the conversation so far has really emphasized two features of schizophrenia that deserve special attention. the first as corey and judy have mentioned t is a disorder of brain development. and the second as steve emphasized is a disorder of cognition. and these two processes or features that come together in an abnormallality called disturbance in working memory which is frequently found in the illness. in fact i think danny mentioned his problems during the day of being able to plan his day. and that likely represents the challenge that he faces due to impairment in working memory. working memory can be thought of as the ability to keep in mind for a short period of time information that is needed to guide thought or behavior.

so right now i am using working memory as i'm keeping in mind the point that i want to make so that hopefully what i am about to say will follow logically from what i have just said. >> so far, so good. >> good. now one of the interesting things that about working memory is that working memory ability develops from childhood through the late teens. so we progressively get better in our working memory ability during that time. recent studies have shown that at age 7 individuals who 10 or 15 years later will be diagnosed with schizophrenia have normal working memory. but by age 13, their working memory ability has fallen below, well below where it should be for that stage of development. so the question really becomes, what is it, what's the neurosubstraight that happens during development that underlies these impairments in working memory. we know from a number of studies that working memory depends upon circuitry,

neuroconnections that are present in a part of the brain called the prefrontal cortex which can think of the area of the brain behind your forehead. the first image shows the location of the prefrontal cortex. and then within that brain region as i mentioned there are specific circuits. and among these skirteds a key component is a type of neuron called a paran -- so named because its cell body is roughly shaped like a try ang el. from those cells there are two types of processes that extend from them. the first called are called dendrites, the partials of the cell where information from other neurons is received. and then that information is conveyed from the paramital cell along the axeon. and at the end of the axeon there is a specialized area of the brain called a synapse. and at the synapse information is conveyed from one paramital cell in this case to another. most of those connections, most of the synapses on its

cells are on their dendrites on small protrusions called dendritic spines. so one can roughly think of the number of dendritic spines as a measure of the amount and the richness of information that a paramital cell receives. now the dendritc spines on paramital cells begin to form in the third period of gestation from that period of time the number of these rapidly expands. in fact, it goes to a number that is much higher than what is present in the adult brain. age then in adolescence, the number of spines are reduced and thought that the spines and synapses on these spines that go away are ones that have not been incorporate mood functional brain circuitry. so for example in the prefrontal cortex they're the ones that aren't actually helping working memory. so prevailing hypothesis in schizophrenia is that this

pruning of the spines goes awry. so that as illustrated here, in the brain of an individual schizophrenia, in the prefrontal cortex, the cells have a much smaller number of dendtric spines. consequence, they are much lessen riched for conveying information and we think that this is what underlies the impairments in working memory that are part of the core cognitive processes that are impaired in the illness. >> this is a pre have found set of findings, presentsed. because first of tall shows a general principles of brain development, overproduction and pruning. one develops many more connections than when ultimately needs and those that are useful to maintained and those that are not are cut back, number one. number two, you see that in

schizophrenia there is an excessive pruning. so you have fewer connections. so this is exactly what you would expect if you don't have a good working memory. you don't have enough connections to give you adequate working memory. you could also see how difficult this might be to treat it because there is not simply a functional defect. you're lacking a piece of anatomy there. so we have to think of some way of either intervening extremely early while the pruning is still going on. or getting some compounds that actually stimulate knew outgrowth of the spines. >> talk about with danny some search, new searches, some new searches for either therapeutic approaches or -- >> charlie, so just to reiterate a few points that eric made earlier, that first generation of anti-psychotics were discovered really by accident in the 50s. they did have a profound affect of reducing positive symptoms. and that was very much the stimulus for getting alot of

patients out of psychiatric hospitals in those days. >> may i interrupt you. >> it really raises an interesting point. it a implies that the positive symptoms are probably not caused by anatomical changes but by functional changes that are so easily reversed. how rapidly can you get a reversal of positive symptoms. >> there's some debate about that. the drugs work within weak weeks but probably get better over the course of about 3 or 4 months. some arguments to and from in terms of how quickly they work. but they work pretty quickly so those first generation compounds were followed by a lot of imitators in the-- class, the a drug called haldol was commonly used. but as we've discussed previously, those drugs have a lot of side effects. and mostly these neurological side effects, motor stiffness, parkinsonian like symptoms, tremor, very much like patients that have parkinson's disease. primarily was not only with

were they producing their therapeutic affects by block dopamines but also producing their side effects. there's that proverbial synapse. you see the presynaptic membrane releasing neurotransmitter n this case dopamine, physically binding to these receptors. the post synaptic membrane which is a kind of communication, chemical communication that goes on. and virtually all anti-psychotic drugs block those dopamine receptors to produce their desirable affects. it turns out there are multiple dopamine pathways in the brain. and in fact two of them are very important for the anti-psychotic affects of these drugs. let me also mention that the newer generation of compounds of anti-psychotic drugs that have fewer side effects, particularly extra par amytal or neurological side effects block other receptors too. they block receptors for

another neurotransmitter called certificate a tonin, very potently. we think it is the pleatropic effect that accounts for their improved therapeutic factors and certainly their side-effect profile. now you can see the two main dopamine pathways i've been referring to, one is the mesolimbic pathway shown there which refers to the court i cole. many of the regions that they have eluded to that are involved in the core symptoms of schizophrenia. and in that pathway that we think these anti-psychotic drugs are producing their desirable therapeutic effects. the dopamine pathway that begins in a little area of the brain called a sub stantia niagara projects to areas of the brain we called basal ganglia. that's the pathway that degenerate whence people get parkinson's disease, okay. these drugs, unfortunately, block that pathway too and produce the side effects. now interestingly enough the

newer generation of molecules actually danny's medicine, a drug called clozaril spares that pathway and only really works on that messo limbic pathway and that's why we think clozapine has other side effects that we're worried about but produces far fewer of those neurological side effects. and patients take those drugs much more regularly than they do the ones that produce those neurological side effects. they're not easy side effects. patients with schizophrenia treated with the older generation of medicines generally stop taking their medicines. very poor compliance. and then almost invariably their symptoms return. they become sick again and often unfortunately have to be hospitalized. now -- >> are there metabolic side effects. >> very important point well. have sort of traded side effects. we've traded the neurological side effects, the parkinsonian side effects i talked about with

other side effects. the newer generation caused a lot of weight gain and patients can actually get type ii diabetes. they get insulin resist tense, their blood glucose rises, that can be a problem so it's kind of a trade-off. we do not have a perfect medicine yet. and as i indicated earlier we don't really have a medicine that helps significantly on those negative symptoms and the cognitive symptoms that are often the most disabling and pernicious. >> how much pain dow feel? >> i don't really feel any pain. >> rose: none at all. >> none at all. >> rose: solis ening to this conversation, tell me your own observations. >> well, i did specialize in neuroscience. >> rose: i know, that's why i'm asking. >> i see so much potential in finding the magic bullet anti-psychotic and a plaud them for their work. and i think we need more researchers doing some more

work so we kim prove the chances of improving the lives of millions of people. >> as one who is a novice to all of this and certainly i am struck by consistently whether it is talking about schizophrenia or alzheimer or other kinds of things, and other cancer s finding the right pathway that provides you the beginning of what you can do. >> yeah. >> i think there are three key questions in related to how do we move from this serendipitous drug discover that has characterized the treatment of schizophrenia today to a rational treatment that's based upon an understanding. basically we need to know what molecules in the brain should we target. >> right. >> when should we administer them. and whom should receive any particular type of treatment. >> and the pathways involved. >> and i think to start with the first question, you know, we need to know what

molecules in the brain are involved in the disease process such that they represent drug target that we could change their action and modify the disease course. so for example, are there molecules in dendritic spines that we could target in such a way so that we could help preserve the spines and synapses that they form and maintain the integrity of the neurocircuit three that is necessary. if we had such an intervention, of course, the next question becomes well, when do we administer it. how early in life do we need to be able to identify people who are likely to go on to develop schizophrenia in order to make this intervention. and then the third critical question is given that as we've talked about, there are different causes of schizophrenia, different types of schizophrenia, how do we identify which individual is most likely to benefitted from a given type of intervention. i think all of those

questions hinge on improving our ability to use biomarkers, measures that can be made in living individuals that tell us something about the underlying biology and that we can use to then choose a new treatment and to monitor how well that treatment is working. >> at this level of the conversation, give me some sense of where your own understanding of the genetic input is a factor here. >> the main thing to think about when you think about the genetics is how you can build that to get at the next level of understanding. the genes themselves are just passed on from generation to generation. they're being use food build something, to build a brain to build the parts of the brain that are functioningment and they're ultimately at least in some cases not carrying out the function that they are supposed to be doing when people have schizophrenia. so you have to be able to tie this together, moving from the genes, through the

developmental processes, through the different cells, through the groups of cells that are connected together and the synapses to make some sort of a breakthrough. and what ought to be possible by having the genes is to be able to compare what one gene does to those different processes. it's very hard to compare an a dument human being to any other adult human being. there are so many differences in our genes and in our experiences and our environments that makes it comparable. but if you can simplify the system so that you can say i know that this one gene, there are certain changes that might give you a 25% chance of schizophrenia. what makes that different. what's different about a nerve cell that has that or doesn't have that. what's different about a brain region if the nerve cell does or don't have that. can we see differences in mice that do or don't have that that would give us ideas about how to look for

other kinds of changes when we can look at the whole brain together. we can't compare ourselves in that way. we have to simplify the system of scientists right now and the genes give us the tools for making that comparison. >> the genes would be so powerful from many points of views. in the simplist case you could do prenatal screening. in down's syndrome we can screen before birth to see whether or not the child going to be predisposed to down syndrome. we could be in a position to identify the six genes or 20 genes that are contributors and see whether the mother is carrying some combination that could be critical. and be prepared for that. or decide not to have that child. s this's number one, number two as crory pointed out once we have identified specific genes we can put them into animal models and we can see, you know, which component of the illness is mediated by which particular gene and develop drugs in mice that overcome that is

hafing a genetic base would be-- a giant step forward and we far from it but we see how to go. >> charlie there may be no single drug that treats the entire spectrum. so right now, for example, pharmaceutical companies and biotech companies are working to find drugs that will work on the cognitive deficits and negative symptoms to add to the other earlier generation of drugs. so we'll think about it much like we treat cancer now. with as complex as its brain is and as complex as the indices s i'm not surprised that this will be actually the path that we'll ultimately lead to better drugs. >> go ahead. >> i think while our discussion has a able to emphasize the use of current drugs and the development of better drugs for the treatment of schizophrenia it is important to recognize that there are other ways that are nonpharmacological that can be used to help improve brain function. and so there are studies being done now using a form

of psycho therapy called cognitive therapy which is showing improvement. >> the same guy you had on this program is now focusing on schizophrenia. and he's focusing on exactly what bothers him. i would like to get the two of them together because he's focus on negative symptoms and also on the motivation. it's very interesting. i'm curious to ask you this because one thing that is mondayly described in schizophrenic people is in terms of their motivational deficit it has two components. wanting and liking. so if i ask you to come to dinner tonight, you might say you didn't say that, but you might say owe oh it's a schlepp t is so far down tourntion i don't want to do it but once you get there, you sit down, and you enjoy the meal as much as i do. so you may schizophrenic people don't have the vision to realize that once they get there it is an enjoyable experience because they think of how much effort is involved in getting there.

so you know, to be able to get drugs that affect that specifically would be very, very nice. >> i'm always interested in the last question i always ask which is what would be the breakthrough that you hope to see. what would be the one thing, one question you would like to see answered? >> i think to get a from my perspect tough have a neurocircuitry basis for understanding the disease process of schizophrenia. that is at the level of cells, the molecules within the cells that are the substraight for brain functions like working memory that is disturbed in the illness, what is actually the biological basis there. >> and how close do you think we are to finding that? >> closer than we were before. >> one of the challenges of schizophrenia is not only the disease is so complex but the organ that is affected is -- >> and the component of the organ. >> exactly. >> these are the highest mental processes. >> rights. >> well, i think that understanding where things

go wrong in a common pathway, very early in brain development f we understood the mechanisms, we might end up with a kind of stat enthat would be preventive for many different disorders. that is my vision. >> dharlie i think understanding the genetic as well as the nongenetic factors that cause the disease would be the breakthrough that we need remember as cory mentioned, even if you inherit the identical dna from your twin that has schizophrenia, you only have a 50% chance of getting schizophrenia. so there are some powerful modifying affects either of the environment or other genes or who knows. if we could understand i think we would be able to craft much better treatments. >> i think it would be positive to have a national discourt about schizophrenia similar to what we have with autism and breast cancer and i think would be a step in the right direction to solving many of these problems. >> why has autism risen to such intense concern and --

>> because there is the feeling that it's increasing in its incidence, some of this may be real, some of imagined. it was not known to exist as a disease until the 1940s. and the diagnosis is increased dramatically in the last ten years. this is for a variety of reasons. there are various services that are available to kids with autism so that diagnosis off sen put on them in order to make services available but there may be an actual increase in incidents. >> that is the statistical observation you can make s it not. >> yes, yes. >> what question do you most want to see answered here, what i assume is a genetic one. >> no one could be more interested in and committed to the idea of using basic science and genetics and animals to study diseases than i am. and i do believe that we'll get rewards from that. but i also think partnerships between the patients and the scientists and doctors are going to be a place where big advances are made.

that really drawing in everyone who affected is gok really important. >> it is probably a uniquely human disease. >> absolutely. >> that is why-- let me just say, danny, i how good it is to have you here when eric conceived this idea for a series in terms of-- and we basically, he did, had the notion that it would be so helpful and so conductive, we thought to have from the experience of someone who was living with the disease to come to this table. and it takes i think an element of courage and it takes an element of warning to make a contribution. so you are exactly what we had in mind when this series was conceived. so if your friends ask why you are on the charlie rose show o you tell them because we need you. all right. >> thank you. >> thank you. >> thank you. >> so eric thank you very much.

so what we look to next. >> next time we're going to do autism, a natural followup to this. because the term came out of the study of schizophrenia and there are dramatic differences between also some overlap between autism and schizophrenia as judy pointed out so it is a natural progression. >> thank you, thank you. steven. >> thank youness. >> thank you very much. >> great to see you. >> thank you. >> thank you for joining us. we look forward to seeing you again on the next episode of our brain series 2. captioning sponsored by rose communications captioned by media access group at wgbh access.wgbh.org

>> the charl career rose brain series is about the most exciting experience of our time, understanding the brain. series is made possible by a grant from the siemens foundation. their mission is to advance the fron tears of research in the basic sciences and mathematics. funding for charlie rose has been provided by the coca-cola company supporting this program since 200 -- and american express. additional funding provided by these funders