skiers is made possible by a grant from the simons foundation. there mission is to advance the frontiers of research in the basic sciences and mathematics. funding for charl-year rose was provided by the following: captioning sponsored by rose communications from our studios in new york city, this is charlie rose. . >> rose: tonight we continue our study of the human brain examining one of its most devastating diseases, skets friendia. schizophrenia is a flex mental disor marked by disturbance of perception, cognition, emotions and mode of behaviours. its symptoms vary from delusions and hallucinations to disorganized thoughts or behavior. despite areas of intense study the origins and development skits februaryia remai a mess-- mystery. we cannot recognize it in physical features in 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 disease's devastating effects it is estimated that 1% of americans suffer from schizophrenia. it usually strikes in late adolescents or early adulthood without regard to class, race, gender or culture. everyone from the writer jack kerouac andbrian wilson and john nash has 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 stephen paul, director of the arlz aldz disease resear institute and a pfess at corll medal clegeorneia bargmann is a professor at rockefeller university. judith rab o port is chief of the child psychiatry branch at the national institute of mental health. david lewis is a professor of translational neuroskeins and chairman of the department of psychiatry at the university 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 journal snae. >> we going to speak about psychatri illnesses today. in the last programs we spoke about neurological illnesses, disorders of consciouses, of cognition. today we're going to talk about psychiatric illnesses and the most devastating of all, schizophrenia. and 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 is fairly common. 1 percent of the population worldwide suffers from schizophrenia. two, the disease affects people early in their lives. and often is nonremiing, sit is with themor he restf 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 different psychiatric illnesses were there, were all psychotic illnesses, category,ubcategies of one or were there many different once. and our first hero was the one without 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. you can see what are the nature of the symptoms the disease has, was's the course of the disease over time, and what's the final outcome. and when he looked at psychotic illnesses from that point of view, which he focused on, heound he could divide theminto 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 ya, alzheimer disease because this starts much earlier. about it is 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-- of the patient an it's noemitting. he called disorders of mood manic-depressive disorders and saw them very different. the major symptoms were feeling terrificably good, hypereuphoric, feeling sad that unlike schizophrenia, there were remissions in which people really functioned quite well. and often althou not invariably the outcome was good. the disphinx teen-- distinction between these two major psychotic disorders although there is overlap has carried forth this day. we still practice-- psychiatry. so he's the scientific founder of the field. however, a number of people particularly eugene bloyler objected to the conception of dementia precox and 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 patient was developed the disease later in life, not necessarily early. d he s a number of patient was did well with the disease after many areas. 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. and 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-- a french chemist began to develop an anti-histamiti compound that turned out to be useful in the treatment of schizophrenia. this is a complete accident and a number of drugs developed in the early phases of developing a psycho pharmacology treatment for psychiatric disorders came out serendipitously. rone poll oy wthe fit company to discover anti-histiminics learning these are good for allergic diseases but the trouble with the earlies once had is side effects so they asked them 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 clinical trials, people were amazed at how calm the patients were. they were much more relaxed than they had been befo. and the there were two very astute french psychiatrists noticed that if psychotic patient its, particularly schizophrenic patients took it, it was like a magic bullet. they stopped hallucinating, having deleeuw'ses-- delusions, kim to the undered states n a short period of time, the fda approved it and by 1954, this was introduced in the 1950s. by 1954, two million people had tried this. and this was one of the major reasons why so many at the state hospitals were emtied 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 paced upon trying to improve what was the first generation it was really empirical instead of having a profound ununderstanding of the disease. but now as you learned, we really beginning to understand the beginnings of a scientific basis o schizophrenia. antherefore 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 where psychiatry is and where it's going as a result of this discussion today. >> rose: so we should begin with stephen paul, and give us a clinical description here 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 subdivided these into three categories or three clusters or dimensions of symoms. the positive symptoms, the negative symptoms and the 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 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 hallucination. these can be visual in nature. but often they are auditory. patients who have sczophreniahearoices whe 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 are very troubling symptoms, you know, for patients with schizophrenia, but very common. now positive symptoms also include delusions. these are false beliefs. beliefs that patient has when there is absolutely no real evidence that is such a belf real. anthese 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 are you a patient with schizophrenia. other common delusions that are experienced by schizophrenics, weall these delusions of reference or control. patients often feel that they're getting messages, 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 have special powers. so forth nationally as eric mentioned, most of the drugs thatwe have tayor many patients, if notost 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 of schizophrenia and cognitive symptoms. and these are the most pernicious and difficult symptoms to treat. andhe medicines don't work very well at all for these. negative symptoms refer really to the absence of normal behaviors that most normal people, healthy people experience. a lack of energy, 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 symptomology ofhe disease. and are very, as i said earer, ry dficu symptoms to treat. and finally, we have the cognitive symptoms it of the disorder. the dementia, dementia precox as eric referred to. patients with schizophrenia have inability, 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 are impaired with what we call ecutive 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 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 y foraving me. we have dan 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 ten advance placement course and i scored in the top 5% in nine of them. 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 decided to go to georgia tech. and in my first year there i got a 4.0 grade 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 t 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 secret code so nobody else could steal my ideas. after a day of writing i slip in addition full psychosis and i had to be returned to america. whale i was on the plane back to america, i thought i saw the devil three times. and i thought i was being sent into 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 sow put me on the anti-is psychotic clozapine and the difference was like night and day. and i was able to return to georgia tech. 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 into a dissertation so i went to the university of pittsburgh to be in the nter for the neurobasis of cognition and i took a class in neurobiology and sat if the back of the class. and i could understand nothing from that class. is so i had to leave the ph.d program in disgrace. when i left at that point, nobody would hire a graduate school dropout. so i had to spend a year at sears selling tvs. i've gone between-- i've gone between unemployment and contracting jobs and i suffer from anxiety, depression. i have is suicidal thoughts. and-- it's tough. but. >> despite that you are able to have a meaningful relationship with your wife. >> i m i have a wife, monday ca, and i love her very much. i have a job doing work in medical coding and i'm able to multitask a do pretty well. so i do have a lot of things going for me in my life. >> danny, tell us a little bit about 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 symptoms since you first became ill. >> well, i mentioned my delusions of grandeur, that is the main source of my positive symptoms. the negative symptoms though arehat holdse back. you mentioned executive functioning. and i am unable to manage the course of my day very well. i spent 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. >> if 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 are 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 happenng. >> rose: they told you the diagnosis and you accepted it. >> yes. and there is a great stigma associated with schizophrenia is so it's hard to not being able to tell friends and family about what is going on. >> rose: 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 b able to hold a conversation with somebody and have them realize that it's a neurological disease. and not something that makes me crazy. >> it's a brain disorder. >> definitely. >> this is amazing. >> rose: it really is. >> its stigma is still associated with the disease. everyone knows this is a disease of the brain. you're not-- there is not bad behavior on your part. >> rose: what is the hope of drugs here? >> well, we hope to get beter drs. 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 is called clozapine, it is something we call an atypical anti-psychotic in contrast to that first generation. >> drugs that first came along were effective for the craziness of the brain, the positive symptoms but had very bad side effects. it looked like parkinson's side affects so people began toet some insight on how hey worked they wked through the dopaminitric center and blocked certain reseptemberers. so using that idea, people tried to develop drugs that don't have those side effects. and that is what is called the second generation of anti-psychotics. >> rose: let's turn to the genetics, understanding the genetic basis of 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 entialtwin with schizophrenia. then would you have about a 50% chance of developing that disorder in your life. and that is true even if you are not raised in the same family, even if they are adopted twins raised separately. and it tells you that there is some sort of a genetic risk, much higher than the risk to the population, of about 1%. but it also tells you that those genes can't be acting enlo. because it is not 100% either. there are interaction between genetic risks and the environment. now a big piece of progress that has happened in schizophrenia in just the past w areas has been understanding something out what tt genetic risk is at the granular level. what kinds of molecules wa, kinds of brain function are different in patients with schizophrenia and unaffected people. and this has been a huge project. it's involved hundreds and thousands of 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 started to tease apart some of the threads of what is happening. so here is one thre tha 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 are still in the womb to set up the development of the brain. so the risk is some sort of a vulnerability that is set up very, very early that makes the brain show problems much, much later. and that same idea comes up from our understanding of enviroental risks too ne of the most well understood environmental risks for schizophrenia was based on the 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 rateses 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 are you in adolescent. not just what happened when you were a teenager or freshman in college. and thewe're learning some other thgs too. there is something about inflammation or the immune system and disease that is important. there is something about certain kinds of electrical excite ability what are called calcium channels that 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 they're sort of lumpers and splitters. they sort of want to say well, all these people are the same. we're going to lump everybody together and say this is schizophrenia, or you can split out different groups. and what we'v discovered fromhe 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 vulnerable 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 genes that create a risk for schizophrenia can create a risk for autism. so here we have thes diffentdiagnoses early diagnosis of autism, adolescent, schizophrenia, different mood disorder, bipolar disease but some of the genes are overlapping. and so we really need to puzzle that apart to reach the next stage of understanding. >> this is really quite fascinating. because-- describes it for what we really call negative symptoms, lack of social interaction, so he had some insight even though one didn't think of autism as a disease, emerged from the 1940s. he really had some insight that this was an aspectf character that can be differentially effective. and corie's point is a very modern point. we thought for a while that these very much as currentlin 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 thing that makes the genetics so hard is it's not like early onset alz alses disease in which su have one genetic defect that cause the whole disease. you have a lot of genes acting together, each having a small effect, procing the syndrome. >> tell us what we have learned from early onset alzheimer. >> well 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 alz alses or breast cancer, for example. first of all n their early development when they were two, three and four, a third of this group of children that we studied were actually seen for what looked like autism-like problems. just as cory was making, a connection we did not expect at all. those tended to improve. and then there would be a few 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 not very specific sort but higher in this group in their early years than in children in general. and a couple of biological markers have kind of leapt out at us over the years. one is that they have a higherateot just in the general public but a higher rate than later onset schizophrenia of genetic abnormallities. pieces of duplication or delusions in the chromosome, too small to see with a microscope called koppy number variance and then just plain chromosomal abnormallities, extra copies or missing ones are just a risk factor even in adult patients. but it's more so in this group. and programs most interesting of all, we've been able to study brain development at a much younger age in people with schizophrenia cause 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 porn. these are only pictures of the cortex of the outer layer of the brain, of course. but inside you can also show with different way of looking at these movie tt all the white matter tacks are basically laid down by the time are you born too. so that the risks such as for infection or famine as corie talked about, can have very major effects 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 th braiwhich is a normal process but where you see this film in red is where the patients who have schizophrenia are way ahead of the healthy controls. 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 which is what you see in a typical adult patient. that's what's 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 seconds when it takes ten years to make them. but the next video shows, which is of the healthy siblings, and what that shows is that earlly in life the healthy siblings have only a small amount of thinning. but by the time they're in mid adolescence it has disappeared completely. and the point of this is that these siblings have a resilient brain. in some ways it gets better. and that may be very interesting what the scientists call phenotype or pattern of brain development to study to see what they do to so to speak shug it off. and that may be one of the most interesting leads we is 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 often as we learn with aldz alzheimer learns a great deal about early onset disease so to take advantage of early onset schizophrenia is a very powerful strategy because we see how many things can go wrong in early brain development, where schizophrenia is one. and from david's work, we understand what is happening inside the brain to account for that. >> there is a psycho physiology of looking at the biological mechanism, yeah? ness yes, charlie. the conversation so far has really emphasized two features of schizophrenia that deserve special attention. the first as cory and judy have mentioned t is a disorder of brain development. and the second as steve emphasized t is a disorder of cognition. and these two processes or features of it come together in an abnormality called a distauschance in working memory freakly found in the illness. in fact i think danny mentioned of his problems during the day of being able to plan his day. that likely represents a challenge that he faces due to impairment in working memory. working memory can be thought of as the ability to keep in mind for ahort riod of time, information that is needed to guide thought or behavior so right now i'm 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. >> okay, good. now one of the interesting things 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. recently studies have shown that at age 7, individuals who10 or 15 years later will be diagnosed with schizophrenia have normal working memory. but by age 13, their working memory ability has fallen well below where it should be for that stage of development. so the question really becomes what is it, what is the neurosubstrate that happens during development that underlies these impairments in work memory. and we know from a number of studies that working memory depends upon circuitry, neareau connections that are present in a part of the brin called the prefrontal cortex which you can think of as the area of the brain kind of behind your forehead. the first image shows the location of the prefrontal cortex. and then within that brain region there, as i mentioned, are specific skirts. and among these circuits a key component is a type of nuferon called a predone eminal neuroso named because its cell body is shaped like a tray angle. and from those cells that will two types of processes that extend from them. the first are called dendrites. these are the portions of the cell where information om other nro received. and then that information is conveyed from the cell along the axe on. and at the end of the axon there is a specialized area of the brain called a synapse. and at the synapse, information is conveyed from one preamital cell to another. most of those connections, most of the synapses on the cells are on their dendrites on small protrusions called dendritic spines. and sone can rohly tnk of th numb of these spines as a measure of the amount and the richness of information that a preamital cell receives. the spines on the cells begin to form during the third trimester of gestation. and from that period of time through the first several years of life, the number of these spines rapidly expands. in fact, it goes to a number that is much higher than what is present in the adult brain. and then in adolescent, the number of the spines are reducednd its thought that the dendritic spines and the sinances that go away, are ones that have not been incorporate mood functional brain skirtry. so for example in the prefrontal cortex they are the ones that aren't actually helping working memory. now prevailing hypothesis in schizophrenia is that this pruning of dendritic spines goes awry so, that as illustrated here, in the brain of an individual with schizophrenia, in the prefrontal cortex, preamital cells have a sller number of dendriti spains an much lessen riched for conveying information and we think it is this abnormality in spines and synapses connectivity that under lies the impairments in, woing memory that are part of the core cognitive processes that are part of the illness. >> there is a very profound set of findings presented. because first of all it shows a general principles of brain development. overproduction and pruning. one develops many more connections then one ultimately needs. and those that are useful, are 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 synaptic 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 because this is not simply a functional defect. are you lacking a piece of anatomy there. so we are going to have to think of some way of either intervening extremely early while the pruning is still going on or getting some compounds that actually simulate new outgrowth of spines. >> rose: talk about with danny some search, these new searches as we referred to earlier, new searches for either therapeutic researches. >> to reiterate a few points that eric made earlier that first generation of anti-sigh couldn'tics were discovered really by accident in the '50s. they did have a profound effect 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 for a second. >> sure. >> it really raises an interesting point. because it implies that the positive symptoms are probably not caused by anatomical changes but by functional changes testimony is so easily reversed. how rapidly you can get a reversal of positive symptoms. >> well, there is some debate about that. the drugs work within weeks but probably get a little bit better over a course of about three or four months. >> uh-huh. >> some arguments to and from in terms of how qukly. but th work pretty quickly. and so those first generation compounds were followed by a lot of imitators in the phenofhiazin, a drug called haldol was commonly used but as we have discussed previously, those drugs have a lot of side fengs and mostly these neurological side effects, motor stiffness, parkinsonian like symptoms, tremor. very much like patients that have parkinson's disease. primarily because not only were they producing their therapeuc effects by blocking dopamine receptors as eric eluded to but also producing their side effects. there is that proverbial synapse, you see the presynaptic membrane releasing neurotransmitters n this case dope minute, physically traversing its synaptic, binning to the dopamine receptors. the post synaptic membrane this is the kind of communication, chemical communication that goes on in the nervous system. and virtually all anti-psychotic drugs block those dopamine receptors to produce their desirable effts. itus out there are multiple dopamine pathways in the brain. and in fact, two of them are very important for the anti-psychotic effects of these drugs. let me also mention that the newer generation of compounds of anti-psychotic drugs that have fewer side effects, particularly extra peramital block other receptors too. they block recementer for another neurotransmitter called certificate atone in, very potently. and we think it is this effect that accounts for their improved thereutic effectand certainly their improved side-effect profile. now you can see that the two main dopamine pathways i have been referring to. one is the mesolimbic pathway which refers to the corticol regions. many of the regions that judy and david have elude odd to that are involved in the core symptoms of schizophrenia. and it is in that pathway we think the anti-psychotic drugs are producing their desirable therapeutic effects. >> the dopamine pathway that begins in a little area of the brain called e substantialia niagara projects to areas of the brain we called was oo gang leah, that is the pathway-- ganglia that, the pathway that degenerates when people get parkinson, these block that pathway too and produce the side effects. now interestingly enough, the newer generation of molecules actually danny's medicine, a drug called clozapine spares that niagara stridal pathway and only really looks on that messolimbic pathway, and that is why we think clozapine has other side effects we're worried about but produces far fewer of the 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 older generation of medicines generally stop taking their medicines, very poor compliance. and then almost invarrably their symptoms return. they become sick again and often, unfortunately v to be hospitalized. now -- >> the metabol side eects. >> very important point so we have sort of traded side effects, really. we have traded the neurological side effects, the parkinsonian side effects i have talked about, with other side effects. the newer generation cause a lot of weight gain and patients can actually get type ii diabetes, insulin resistant, their blood glucose rise 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. >> rose: how much pain dow feel? >> i don't really feel any pain. >> rose: none at all. solis ening to this conversation, tell me your own observations. >> well, i did specialize in neuroscience. i see so much potential in finding the magic bullet anti-psychotic. and i applaud them for their work. and i think we need more researchers doing some more work so we can improve the chances of improving the lives of millions of people. >> rose: as one who is a no advice to all of this and certainly-- novice to all of this, i'm struck by consistently whether it is talking about schizophrenia or alzheimer or other kinds of things, and other cancer, it is finding the right pathway. >> right. >> that provides you the beginning of what you can do. >> uh-huh. >> yeah. >> i think there are three key questionsn reted to how do we move from this serendipitous drug discovery that has characterized the treatment of schizophrenia today to a rational treatment that is based upon an understanding. basically we need to know what molecules in the brain should we target. >> rose: right. >> when should we administer them. and whom should receive any particular type of treatment. >> the pathways involved. >> and i think sort of to start with the first question, we need to know what molecules in the brain are involved in theisea 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 that would help preserve those spines and the synapses that they form. and maintain the integrity of the neurocircuitry that is necessary for the development of working memory. 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 a 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 cause of schizophrenia, there may be different types of schizophrenia, how do we identify which individual is most likely to benefit from a given type of intervention. and i think all of those questions hinge on improving our ability to use biomarkers, measures that can be made in livg 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. >> rose: at this level of the conversation give me a sense of where your understanding of the gennett input is a factor here. >> well, 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 used to build something. they're being us to build a brain, they're being used to build the parts of the brain that are functioning. and they're ultimately at least in some cases notice carrying out the function that they're supposed to be doing in people with 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 ne does to those different processes. it's very hard to compare an adult human being to any other adult human being. there's so many differences in our genes and in our experiences and in our environments that makes us uncomparable. but if you can simplify the system so that you can is 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 is different about a nerve cell that has that or doesn't have that. what is 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 as scientists right now. and the genes give us the tools for making that comparison. >> the genes would be so powerful in many points of view. in the simplist case you could do prenatal screening. in down syndromewe c screen before birth to see whether or not the child is going to be predisposed to downs syndrome. we could be in a decision to identify the six genes or the 20 genes that are contributors and see whether the mother is carreeing some combination that would be critical. and be prepared for that. or decide not to have that child. that's number one. the number two as cory pointed out, once we have identified individual genes, let's say there are six or eight 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. so having a genetic basis of it would be a phenomenal step forward and we are, you know, quite far from it but at least, you know, we see how to go. >> charlie there may be so 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. and so we'll think about it much like we treat cancer now. we as complex as the brain is and as complex as the diseasing is, i'm not surprised that this will be actually the path that will ultimately lead to better drugs. >> go ahead. >> i think while our discussion has appropriately emphasized the use of current drugs and the development of better drugs for the treatment of schizophrenia, it is also important to recognize that there are other ways that are nonpark could logical 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 thepy which is shown improvement. >> the same guy you had on this program is now focus on schizophrenia. and he's focusing on exactly what bothers him am and i would like to get the two of them together. because he's focusing on negative symptoms and also on the motivation. it's very interesting. i'm curious to ask you this. because one thing that is 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 night, you might say you didn't say that but you might say oh, it is so far down town. i don't want to do it. but once you get there, and you sit down, 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 to be able to get drugs that effect that specifically would be very, very nice. >> i'm always interested in sort of last question i always ask which is sort of if there is-- what would be thbreahrou thayou hope to see. what would be the one thing that one question you would like to see answered? >> i think to get from my perspective, have a neurocircuitry basis for understanding the disease process of schizophrenia, that is that the level of cells and the molecules within those cells that are the substrate for brain functions like work memory that disturbed in the illness what is actually the biological basis. >> and how close do you think we are to finding athat? >> well, closer than we were before. but you know i think one of the challenges is schizophrenia is not only the disease complex but the organ that is affected. >> and the component of the organ. these are the highest mental processes. >> well, i think that understanding where things go wrong in a common pathway, very early in brain development if we understood the mechanisms, we might end up with a kind of stat enthat would be prevented from many different disorders that is my vision. >> charlie, i thin derstding the genetic as well as the nongenetic factors that cause the disease would be the breakthrough that we need. a remember as cory mentioned, even if you inherit the identical dna from your twin that has skits friend ya, you only have a 50% chance of getting schizophrenia. so there are some powerful modifying effects either of the environment or other gene or who knows. if we count stand that i think we would be able to craft much better treatments. >> i think it would be positive to have a national discourse about schizophrenia, similar to what we have with autsm and breast cancer and i think it wab a step in the right direction of solving many of these problems. >> why has autism risen to such intense concern and schizophrenia hasn't. >> because it is the feeling that it is increasing in its incidence. some of this may be real, some imagined. it was not known to exist as a disease until the 1940s. and the diagnosis is increased dramatically in the last 10 years. this is for a variety of reasons there are various services that are available to kids with autism so that diagnosis often put on them in order to make services available. but there may be an actual increase in incidence. >> that is a statistical observation you can make s it not. >> yes, yes. >> cory what question dow most want to see answered here, what i assume say genetic one. >> no one could be more interested 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 the docrs are going to be a place where big advances are made. that really are drawing in everyone who is effected as collaborators is going to be really important. >> it probably a uniquely human disease. >> absolutely. >> this is why -- let me just say, danny, how good it is to have you here. when eric conceived this idea for a series in terms of, and we basically, de, had the notion that it would be so helpful and so cotrucve, we thought to have the experience of someone who is living with the disease to come to this table, and it takes i think a hell an element of courage and an element of warning to make a description. so are you exactly what we had in mind when this series was conceived. so if you your friends ask why are you on the charlie rose show, you tell them because we need you. all right? >> thank you. >> thank you. >> so eric thank you very much. so what will we look to next? >>ext time we're gog to do autism. a natural followup to this. because the term came out of the study of schizophrenia. and there are dramatic differences but also some overlap between autism and schizophrenia as judy pointed out. so it is a natural progression. >> thank you, thank you. >> thank you. >> thank you very much. >> thank you. >> great to see 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