 Hi, I'd like to thank Peggy for the introduction and I'd like to thank the audience for sticking to the very end. Just in terms of our clarification about the program, this keynote lecture was going to be presented by Dr. Michal Schwartz from the Weizmann Institute, who last week had a daughter taken to hospital and could not make the trip. So I'm just filling in. I structured the symposium to give myself the last lecture, so that was the easiest way to fill the time. So I hope I don't disappoint you too much. And tomorrow, just to be very clear, we don't come back here to this room. The meeting will finish at the John Curtin School. So there will be no activities here in this building tomorrow. The second day of the conference is at the John Curtin. So please don't come here tomorrow. So as I said in the title, the goal of this presentation is to give people a sneak peek at the future of psychiatry. So these are some pictures from 1961. So that's the car that people would drive back then, was like the latest model, the newest big thing. And this is how the women would dress, and that was what was in fashion back then. This was the present of the United States, men of the year, John Kennedy. And here was Yuri Gagarin flying into space and thereby showing the superiority of the Union of Soviet Socialist Republics and how communism was a much better system than what the Decadent West was embracing. So that was the world of 1961. And of course, in 2001, things have changed a lot. So this is the 2001 Maserati, it's pretty different from the car from 1961. These are the women of 19 of 2011. So this one here is Natalya Vodyanov, who is the person described by historians who has been the most successful in history. So in four years she went from selling potatoes in a village in Russia to own in the city of Westminster and getting one billion dollars in rent from all of London, which belongs to her. And so sometimes they should do other things rather than research. And you can see that the difference in attire is very profound from 1961. And this is the men of the year from Time Magazine, who is not John Kennedy. This is what we are all glued to, and this is where we live now. That's Shanghai, Pudong. But Faulkner said that the past is never dead, it's not even past. And that's very true for the field of psychiatry. For the practice of psychiatry in 2011, 1961 is not dead, it's not even past. So this is Judith Axelrod in 1961 at the NIH. And interestingly enough, he had his labs in initial labs at Building 10, and his area was like a little kind of museum-like, was never renovated, and that's actually where Mali and I were given some space to draw our studies when we were there because people said that lighting never structure lights in the same place. So that space was not very highly desirable. So in 1961, he published a series of three papers, and I just put one of them here for as an example, in which he triturated noradrenaline and adrenaline and showed their kind of fate at the level of the synapses. And that's how he showed the mechanism of synaptic reuptake of monoamines. So this is the, you know, the most simplified version of a neuron you can think, and that's a monoamine going through the neuron, that's, let's say, make the case that serotonin could be noradrenaline as well. And then it would bind to a receptor, and the idea was that it would be destroyed at the level of the synapses by the monoamine oxidases. And what Judas Axelrod showed is that there are transporters that actually bring the secreted monoamine back to the presynaptic neuron. And for that, he got a Nobel Prize in 1970. And if you think about it today, if a patient comes to the doctor with depression and needs a medication, most likely a drug that will be given to that patient is a drug that inhibits the synaptic uptake of a monoamine. Like in the case, he would be serotonin, a reuptake inhibitor that's blocked by the SSRIs. Or if you want to be a little newer, and this is a very recent slide that I found on the internet, this is the serotonin and norepinephrine reuptake inhibitors. So you have the monoamine oxidase here, it's breaking the catecholamines in the synapses. And you have blockade of the reuptake of serotonin and of norepinephrine. So that's the mechanism of action, the initial mechanism of action of valofaxin, duloxetine and denzvalofaxin, which are all relatively recent and current drugs that a patient may very well get if they go to a doctor today. So in summary, as Faulkner said, the past is never dead, it's not even past. This is 2011, but we still practice psychiatry based on the science of 1961. So why aren't current treatments for depression based on the immense neuroscience discoveries of the last 40 years? We've discovered so many transmitters, peptides, neurohormones and receptors and potential targets. And why aren't people treated with medications that are based on those systems? So some people call this a beast between the lab and the clinic, which is not only the exclusive domain of psychiatry happens in every area of medicine. Some people have called this the valley of death, and that's why this whole discipline of translational medicine has been created to foster and accelerate the pathway between one end and the other there, between the lab and the clinic here. And I think that in our case, the valley of death is too nice a name, so I'm calling it a cesspool of devastation. So this is like one of our patients, and this is the tsunami of the broken promises of the neuroscience of the last 50 years. And as you all know, we are launching a new journal between two days tomorrow. And that's kind of tangential to this presentation, but I think it shows that that's a focus of interest at the current time. And so essentially, this is like a summary of where some of our patients are who are refracted to existing treatments. And sometimes where we are is a field in terms of bringing in new things from the bench to the clinic. So how do we go from here to a better place? How can we facilitate translation? How can we go to a place that the grass is really greener? So I found another modern group that's very eloquent about this. So here. Let's take a turn. So what's the sneak peek? What's the future? How can we go from like having made so few translational applications to psychiatry to something that can help people more directly? So why are we stuck in the past? So in my view, the gap has been really the failure of systematic translation. And again, you know, this is the website of the journal, but the problem I think is that I don't believe that if you leave your house like with 20 things to do in a day, you're going to do all 20. You tend to do like the one or two or three that are the most priority to you. And I strongly believe that without an organized field of translational medicine and translational psychiatry in our case, this pathway is not going to be very effective. So you can have, you know, very dedicated and committed and bright and intelligent people doing this. And we've seen a number of them presented today. But if each one is doing it in his or her own silo in an isolated manner from zero, I think we're going to be stuck where we are. So the premise has been in academic medicine in general, that we have to create a new field, a new academic discipline of translational medicine in which people are going to be trained in that area. That's their major professional identity. And that being their major professional identity, that's what they are going to be doing as a priority. And it's not going to be someone who does something else during the day. And then as they are in a hobby or as they are kind of a number 12 item on their daily list is trying to do some a little bit of translation. So in addition to this conference I had organized an international meeting, an international symposium, a conference on translational medicine in general as a field to see what different places and countries are doing. And that was very successful, happened in November. So for that meeting I proposed a new classification for translational medicine. And I used smallpox as an illustrative example because very sadly we don't have too many diseases in which we've gone all the way from initial discovery to global health and eradication of the disease. So I used that smallpox, which is obviously not the psychiatric disorder, as an example to show the complete flow of translation and then how we can intervene at that level. So we think of our disorders as being terrible and schizophrenia, there was an editorial nature that said that it's the worst thing that could happen to a person. But we tend to forget that there are other bad things that medicine has been able to conquer. So this is smallpox, that's a person, a girl that had the pusher in the finger and then people, especially children, scratch the eye and then they become blind. And just to show that it's not something restricted to poor countries, this is from the New York State Department of Health. So smallpox killed 400,000 people in the 18th century, including five reigning monarchs, one of them Louis XV, it caused a third of all blindness, as you saw the very vivid example. And of those infected, 20 to 60% died and over 80% if they were children. And what I find most astonishing is that even though the disease was eradicating the 20th century, so it was coming down by the 80s and 90s, there was no smallpox anymore. In the 20th century alone it killed between 300 and 500 million people. And even as recently as the early 50s, 50 million people died and in 1967, two million people died. That's just before eradication. So it's a disease that began at the north of Africa approximately 10,000 years ago. By the time it spread through the world, so by the time it reached Japan, for example, it killed one third of the population. It killed 80 or 90% of the Native American population. In Australia, the only place in the world that the disease was never endemic, it arrived twice, devastated the aboriginals, but then died out. And there were very successful vaccination campaigns with certification of the eradication in 1980. And it's the only human infectious disease to have been completely eradicated. So this is a very dramatic picture, I think one of the nicest pictures in all of medicine of a very sick mother holding the child who is like happiest could be and nursing and completely healthy thanks to this vaccine here. So the story of the vaccine, which gives an idea of this pathway of translational medicine goes as follows. It was always done with the live virus as the only thing that works. Initially, it was done in China and Turkey with the actual smallpox virus, which is problematic because the person gets sick and is infectious. So then, Jenner, who is the father of immunology, Edward Jenner, he had the idea to do what's called cross immunization. So you use a much less pathogenic virus, but you create antibodies in the person who receives that that protects them against the full blown disease. So on May 14, 1796, and what's very nice about this is that it's all very meticulously described. He had a cow in his backyard called Blossom that had cowpox. This milk made called sirenelms milked the cow and got the much less infectious disease cowpox. He deliberately took the blisters from hair and put them on the arm of his gardener son, James Phipps, who became the first person in the world to be deliberately cross vaccinated against smallpox. And that happened on May 14, 1796. Then on May 8, 1980, almost 184 years to the day, Professor Frank Fenner, who is my predecessor as director, one of my predecessors as director of JCSMR, and actually this, you know, the academy is honoring him this year because it just passed away. So all the scientific lectures presented here have something to do with the theme of his work and are in his honor. So he certified to the, so that's a picture of him certifying to the World Health Organization the global certification of smallpox. And that's 184 years later. So that's a very long process that we cannot just sit and wait for 184 years to go from discovering something or doing some exciting translation on new treatment in a human being proof of concept to actually having eradication of the disease. So, but based on that process that we saw over the 184 years, I have conceptualized a new way to structure translational medicine that it has, it is becoming an academic discipline, but needs, I think, a kind of conceptual academic structure. So other people have described it in three steps, T1 to T23. So I put three more steps that I didn't want to change the names of the ones that were already there. So the first one I had to call T0, so it comes before one. So I call this the initial process of discovery. And what has happened in many parts of the world, including the United States, on the, with the clinical translational science network that exists there that's funded at $500 million a year. And also a very vast program that the UK National Health Research Institute's funding, they have an announcement now this current scheme is going to distribute this year at 600 million pounds in funding for biomedical research centers, translational biomedical research centers. But what I think is that we've become very specialized at creating this very elaborate pipelines, but if there aren't the great discoveries to be translated, it's like a bridge to nowhere. So I think that it's not the case that all fundamental discovery has already take place, a lot of discoveries still need to occur. And I think this kind of initial process of discovery is under emphasized when people talk about translation. And that's what I'm calling a T0. And I think that this process is critical if we are to distinguish translational science from purely applied science or from commercialization. And some people have a very misguided idea that translation is just commercializing something the same way that some people think that all clinical research is just clinical trials, which is absolutely not true. So T1 is a name that has been very widely used by now and refers to the now classical step of bench to bedside. So you have an idea in the bench like what you saw with Fener, you know, poking James Sweeps with the Pusul from Cowpox. That's T1. So it translates some idea that you have into a first in human study. And then T2 is what people call now classical steps of clinical trials. So let's say you had that first vaccination that you saw. Then you have the idea, OK, let's do this in 100 people and see if it really works. So all clinical trials are in this domain of T2. Then there is T3, which is a translation of something into public health guidelines. So for example, Ian Frazier had a brilliant discovery here in Australia of the Papilloma vaccine. And the question is then does it become public health policy or public health guidelines when a 13 year old, 12 year old girl goes to the doctor, GP, does it say you have to get this vaccine and here's the prescription, go get it or he doesn't say it, you know, she doesn't say it. So in the states, there was actually a big situation that the state of Texas made the Papilloma vaccine mandatory and there was tremendous discussion in the country. Then it turned out that some people on the committee that made that recommendation were paid consultants from work. So you kind of throw the baby away with the bathwater. So the vaccine is no longer like mandated. Like when you go to school, in most countries you have to show like your mumps and measles vaccine. So it was in that same category. So it went into that category and now it's no longer in that category. So T3 is that exact domain. Do you make something kind of a mandatory policy or healthcare part of healthcare policy or healthcare guidelines? Then you have T4 because the idea that if you talk to most people they think, okay, you know, you go all the way from discovery to trying to clinical trials. Then it becomes guidelines and then that's the end. So you have it done. But it doesn't end there because a lot of things that we transform into guidelines or practice, you have to really watch that over a long period of time and then look back in a structured way and see if it really worked or not. And many things don't work. So a very good example is hormone replacement therapy for women, which was part of healthcare guidelines. So if women had even moderate, severe of course, but even moderate, sometimes even mild, sometimes even not very significant menopausal symptoms, people would be prescribed HRT. And it's being shown by several studies including some done here by Emily Banks who is a colleague here at ANU. Showing that they increase the health of cancer. So for example, for breast cancer, HRT is estimated to contribute to 9% of cases of breast cancer. And when it was substantially decreased, the rate of breast cancer decreased in the states here in Australia where HRT no longer became part of healthcare practices. So we don't know if an intervention, a medication, or a long-term treatment for something will have very profound adverse reactions down the road. So you need to, once it becomes part of healthcare policy, you have to follow that. You have the Vioxx story in the U.S. There are many other stories in medicine that appear to be very beneficial. When you look at them retrospectively, they are not so beneficial. And T5, which would be the sixth step, is global health. So once something is implemented and then is shown to work on the long-term, we have almost like a moral obligation to then make that part of our global health policy. And the WHO has, for example, like a brief, like a limited number of drugs that they consider essential drugs for neurology, for psychiatry, for the different things. So it should become an essential drug for use in every country if it's something that can be given in mass, it should be done like that. And this further validates effectiveness and utility. So the reason that I use the smallpox example is that you can see this transition there from the initial concept that you saw that painting of Jenner, the first in human, clinical trials. And then in that particular case, after the vaccines effectiveness became health policy in many countries once it was shown to work. And then once after a while, after it was systematically demonstrated to be safe and effective, then there was a concerted global effort that led to the final eradication of the disease. So that's the T5 step. So you can see here that there are six kind of a logical steps for translation. And I think one of the problems in all of medicine, but including psychiatry, is that some people work in one step, some people work in another, one institution does a little bit of something in one area. And I think we really need like a more concerted national or international efforts to follow things along this kind of pathway from discovery to health. And as I said very briefly in the morning, in order to follow that pathway, there tend to be three gaps that's where things get stuck. There are three big glitches. So the first one, as I said, is the knowledge gap. So that's tied up to that T0 concept and that we need to discover new treatments and try to find cures. So if we have practice that's not evidence-based, sometimes it's because there is no evidence. So you cannot go very far in that regard. The gap number two is the practice gap. So evidence exists, but the practice is not evidence-based. So we have some examples. I'll talk about this in a moment and I'll show that sometimes there is very good and very solid evidence that's absolutely irrefutable. We very stubbornly just refuse to pay any attention to it. And then there is what I call the implementation gap, which is that sometimes there is evidence, there is common sense and the practice is evidence and common sense-based, but things don't happen as prescribed. So I gave in the morning the example of the hypertensive person who goes for the first time to a doctor and is overweight and smokes. Every doctor will tell them, you know, lose the weight and stop smoking and that doesn't happen very often. And in our sphere, in psychiatry, you can have people who have either predisposition or having first breaks of schizophrenia or depression and can make very sensible, evidence-based recommendations and people just don't follow them. So going from, so this was like a very general overview of my understanding of some of my new ideas about translational medicine and applying that to the field of psychiatry. So I'll talk a little bit more about depression and be a little bit more specific. So when we think about depression, Malia and I wrote this paper in Nature Reviews Neuroscience 10 years ago that actually still gets cited quite a lot to our surprise. We've been invited to rewrite and update it. So what we have in most of psychiatric disorders and specifically in depression is that you don't have a unified, single, absolutely identical disease that everybody who has that diagnostic label has. You have a collection of syndromes that present more or less the same. So they get this very broad classification and they fit into a very broad label. So you have at the bottom here, depressed syndromes. And you have, leading to that, a host of environmental factors that begin in the prenatal period and then go through all the ones that you know and have studied and have heard about so well. And then if you go to the other side, you have genetic factors. So in principle, hypothetically, conceptually, you could have susceptibility genes of major effect or susceptibility genes of small effect. So at the time, which was still 10 years ago when we put this, I imagine that probably there wouldn't be any susceptibility gene of major effect coming out for depression or if there was any, there would be very few of them. There would be the minority of case. That's why that box is much smaller. And then the most likely scenario would be a host of susceptibility alleles of small effect. So I'll make a little detour here because I study two diseases that some people think has been completely unrelated but I think that there's a lot in common between them. And they are obesity and depression and actually I trained in endocrinology and diabetes before I trained in psychiatry. So very similarly to depression, obesity is a very complex disorder of gene environmental interactions. However, in something that's different from depression, in obesity the vast majority of cases exactly what we deal with all the psychiatric disorders that there are lots of small, I know alleles of small effect and lots of environmental factors and it's very hard to parcel those out. But in obesity as opposed to depression there are some very rare cases in which there is a major effect gene that accounts for essentially causes the disease. And those very rare cases point out to new pathways and give us novel insights into human biology. So when studying these very rare cases I'm often asked, why do you spend your time like studying and like conditions that affects 20 people in the world? But what people tend to forget is that for example the statins are among the most commonly used drugs today and the discoveries that led to that made a very major way by Brownstein and Brown and Goldstein in Dallas. They were, the initial studies were of these families with very rare kinds of hypercholesterolemia and they are kind of very specific genetic mutations led to the elucidation of the pathways that then became the targets for the statins. So sometimes understanding a rare case of a disease can lead you to get new insights into the biology that can lead to new treatments that will help people who have the common and complex form of the disease. So for obesity one of the key genes in the regulation of body weight is the leptin gene. So there was, people knew the existence of these mouse, this is the cover of nature in 94, this is from our own lab. So this is the OB mouse that has a Mendelian recessive mutation and when the mouse gets two copies of the mutated gene it's very heavy and it's a lot and has no satiety and becomes far heavier than either true normal weight mice or even four mice that have a knockout of IL-1 receptor antagonist. So these animals have more IL-1 action, they are leaner and leptin is made in the fat cells. It sends a signal to the hypothalamus to decrease food intake and increase energy expenditure thereby decreasing food body weight. So I've been since 1998 and it's a long and complicated story. I can tell people in coffee break or drinks, et cetera, how we got to that. But I've been studying since 1998 a Turkish family that has a Mendelian recessive mutation that makes their leptin molecule exactly identical to that of the OB mouse, which is a truncated non-functional molecule. So this family had three adults who are the only three people identified in adulthood with a leptin gene mutation. And they were very obese when they began treatment. So I brought them from Turkey to the General Clinical Research Center at the University of California in UCLA and they were there for 13 months. So this is a graph of their body weight and how they lost the weight and here how food intake decreased acutely but then went back to baseline but they continued to lose weight even as food intake is going up. You see food intake is going up here and weight's going down here. But you see that it's energy expenditure and it increased continuously during this period of time. So initially they lose weight because they eat less and then they continue to lose weight because they spend more energy. And I could talk a lot about the treatment of these patients but it summarized in this video that I made out of clips when the story broke out in the States. So it's all summarized here. These three Turkish cousins, Byram, Zeynep and Elif, may help you lose weight. Not with a new diet or exercise video but in the world of medical research. They may hold a genetic key to the elusive mystery of weight loss. Turns out the cousins are ideal research subjects. For all intents and purposes it's as if their body never gets a signal that they have enough food. So from when they are born they begin eating very voraciously and they eat large amounts of food and they become very obese for the life. Cousins are from a village in Turkey. They flew to Los Angeles to be studied and treated by doctors at UCLA Medical Center for a rare disorder. They are the only known adults in the world with a genetic mutation preventing their bodies from producing the hormone leptin. When given daily leptin injections over 10 months 313 pound by Ron Donsat lost 146 pounds. Elif Fakili weighed in at 231 pounds. She lost 90. And Zeynep Fakili weighed just shy of 300 pounds. She lost 93. So every day for the past 10 months the cousins have injected themselves with small amounts of leptin. They exercise moderately but haven't restricted their eating. Here Zeynep and Elif try on their old dresses. The women have each lost 90 pounds. Byram with his old pants has lost almost 150 pounds. This is a monumental occasion. The cousins lost way in before returning to Turkey where they will continue their leptin replacement therapy. Their lives have been changed forever. So happy you cannot imagine. They feel very healthy, very happy. They think that they can have a normal lifespan and they are really very different from when they first came here. I've never seen a case like this before. And leptin is a well-known protein but we really haven't known sort of how to apply it in the medical sense. This family is really sort of pure science and that we know we replace it, they lose weight. Now for other people, the leptin question means are there other proteins? Are there other enzymes will interact differently? What's the role of insulin? How do the fat cells work? So it's a piece of the puzzle but we're certainly not done yet. Much more research must be done to determine if leptin can be an effective treatment for obesity but for Byram the results are unmistakable. When he flew to the U.S. last year he needed two airplane seats. He's leaving in one. Tracy Potts, NBC News, Los Angeles. So this is a summary of the actual numbers of what you just saw. So patient A is the man, B is the younger woman and C is the older woman. So here is the weight in kilos and you can see that the man had his weight more than half. So he went down more than 50%. And the women lost a substantial amount of weight but not as much. And it's unclear if it's because they are older than the man or if it's just a function of the sex or some other factors. And so percentage body fat, the man began with 43% and ended at 10%. So after we studied these patients or while we were studying them but the study had already begun for a few years we found in the same family a young boy who was two when he was first identified and when he came to us he was five. So what I showed you initially before was the simplified pedigree. If you look at the full pedigree there were at the time that I put his numbers there, 19 normal weight members of the family who hadn't had children yet. So the bottom of the pedigree was an N of 19 and 19 are alive. So it's not that they live in a small like a rural region of Turkey but it's just to show that it's not that they are dying of a lot of things that could be happening there. N of 12 in the same environment with the obese phenotype, eight died early on of febrile illness. So the odds ratio of death in the absence of leptin is 25.4 and as I said death is due to immune deficits. So we brought this patient, the boy to Los Angeles and I had an idea to film him actually eating in the absence and then in the presence of leptin which I hadn't done with the adults. I mean, I saw the change but I can report it to people but you cannot see it. So this is the last day before the boy was treated. So there's the treatments at night so in the evenings that they get the injection. So this is his last lunch before leptin. So he chooses the food, he went to the cafeteria, he chose the food, you can see he's five years old, he weighs 50 kilos. That's the activity watch that I showed you the graph from before for the other patients and the protocol there was that he would eat for 10 minutes and would be filmed. So and I clip that 10 minutes is one minute and then it's 10 minutes later and that's clipped to one minute as well. So in this 10 minutes, and most of you have a psychiatrist or have an interest in psychiatry, so look at his affect, his concentration, how he's completely focused on the food and at the end the nurse actually has to take the fork away from his hand and drag the food away from him at the end of the 10 minutes and it shows absolutely no evidence of satiety. So then 10 days later, after one daily dose of leptin for 10 days, the food that he chose before is here which is untouched and this is what he wants to eat now which is a very different change from before but now look at his affect, his concentration, his level of cognition related to the food over that one minute and you'll see that in the course of that what's very interesting is that he wants to get out of there he doesn't want to eat at all and we say you have to stay here for 10 minutes and remember that the fork had to be pulled out of his hand and now he puts it there and in a few seconds it's gonna have a temper tantrum asking to be pulled, you know to get out of there and go and play. So you can see it's a very dramatic change in behavior with just 10 doses of hormone replacement. So then this is the boy in 2008 and that's the same boy in 2009. So going back to the point of how sometimes that gene of major effect can give us a new insight into biology, it's pretty obvious from the picture with the boy and we talk about translation going all the way from bench to bedside but very often it's very good to go back from clinic back to the bench and to initial discovery. So it's very obvious that the brain is processing information related to food very differently in the on leptin state versus the off leptin state. So in the adults we've been doing a protocol for several years that we bring them to studies once a year from Turkey back to the US and hopefully at some point soon to Australia and then we take them off leptin for six weeks and then we can study them on leptin, off leptin which is the only human model of absence of leptin so you can see its effects and then you put them back on leptin again. So we did that in collaboration with E.D. London during FMRI and presenting them a visual cues related to food and in the off leptin state when they are hungry the insula lights up which has been an area that has not been traditionally tied up substantially to food intake before. So the same one year after we published that a group from the Montreal Neurological Institute did the opposite experiment that they gave a hormone that its presence increases food intake. So leptin suppresses food intake so its absence increases food intake. The presence of ghrelin increases food intake. So they gave ghrelin which is an orexigenic hormone and did FMRI with food related cues and one of the areas that came up positive was the insula exactly the same region that our patients had come up in the absence of leptin. And then at that same time in addition to these two studies Damasia's group had a paper in Science that in which had identified 20 people who had micro-infarcts similar to what was presented earlier by Sajev but affecting the insula and those people had been heavy smokers their whole lives and had never been able to stop smoking but with damage to the insula they could stop cigarette smoking very easily. So in the insula lesion, a lesion there decreases cigarette smoking. So you would assume that activation would facilitate smoking and addiction. And then the insula is activated in the off leptin state as you can see to the left there and underneath in the on ghrelin state. So is insula activity facilitating food intake and obesity? So this is a good example of how you can go from a rare single gene phenotype to insights into brain function that are applicable in more general terms. So going back to depression sadly for the psychiatric disorders no genes of major effect have been identified yet. So we cannot say okay we have this rare family here that has this gene of major effect that affects a pathway that's related to mood and then let's develop a drug or intervention or get better understanding of depression because of this rare case. I hope we find some at some point in the future. So in the absence of that we have been treating people as I said with this very old fashioned armamentarium that includes drugs whose principles have been identified for over 50 years. There are non-pharmacological approaches that were presented here earlier including ECT, transmagnetic stimulation, vagal nerve stimulation. Then there are other targets like neuropeptidermic strategies that have not been particularly fruitful but are still substance free. I think it's pretty much killed as a drug but CRH there is still some hope there. And then there are different drug targets like melatonin, glutamate, crab, BDNF, reward circuits. And you can put another little square here and try to do a little bit of translation there. But what we have done in our own work is to go kind of orthogonally and look at pharmacogenomics as a way to identify new targets and individualized treatment. So this is by now a note slide from Alan Roses that just shows the full scope of genetic testing showing the difference between genetics which you're trying to identify what's causing the disease versus pharmacogenetics in which you're trying to identify optimal drug response. And in both case you can have rare genes that have a causal effect like what you just saw for leptin or you can have what's more common which are allelic variants, each one of a very small effect. And that same parallel would apply to pharmacogenetics. So I'll just give you a brief overview of the pharmacogenomics of depression which is what we study and go from that summary to give you which is a review we've just published, just publishing now. And from there, like I'll present a whole field as a whole and then go to the specifics of our own work. So I had talked before about this translational gaps and they are very nicely illustrated here. So I'll not talk about the gap three, the implementation, but the first two gaps. You have in this first gap, it's the problem is the knowledge. So the replicability and robustness of findings. So other findings really strong enough to become, to be the evidence for evidence-based medicine. So when it doesn't seem to be the case. And the second gap is when you have findings that are very robust, but then they don't make them to clinical use. So when you think of pharmacogenetics, there are two domains there. The first one is that everything that happens to the substance, to the chemical from when it enters your blood in a tablet or in a drug format, then it circulates, goes through the liver, goes through the blood-brain barrier and reaches the brain. So any gene that affects anything here is in the domain of pharmacokinetics. And that includes the genetics of drug absorption and the genetics of drug disposition. And then let's say when the drug enters the brain and it's in front of a neuron, then what happens at that level is in the domain of a pharmacodynamics. So here, for example, is a transporter. So a variation in the serotonin-transporter gene, which's been very well-studied in depression or pharmacogenetics or depression, would be in this domain here of a pharmacodynamics. So the problem is pharmacokinetics is that the knowledge exists is very robust. The evidence is there, but it's just not used. And here we don't have the evidence as much as we would like to. So I'll begin with the second gap, which is kind of short and I'll make just a couple of minutes brief story here. So the translational gap number two is the, is when we have the knowledge and we don't use it. So the liver metabolizes drugs and there is a family of enzymes called cytochrome P450. And here is their actual amount in the body. And so 3A4 is the most common. Here's the chemical structure. Here's their abundance. But 2D6 and 2C19 are very important because they metabolize the highest number of drugs that are more relevant to us. So 2D6, UIP 2D6 metabolize 50% of the 100 best-selling drugs in the United States. And there is a chip that went on the market and was a commercial flop, probably because of a pricing. I think it's a pricing and a translational gap issue, a combination of both. But the chip exists, it can test for this. Nobody disagrees that if someone has, is a low metabolizer for a specific enzyme, the drug is going to accumulate in their system and they're gonna have more side effects. Or if they're ultra rapid metabolizer, they'll break down the drug quicker and they would need a higher dose. So that's not a question, but we don't use that information at all in practice. So Julia Kirchheiner published this paper in Molecular Psychiatry a few years back. We were both Malia and I were co-authors. And she went over the very carefully, documented and uncontroversable evidence. And even made specific dose adjustment recommendations for different drugs. So some of them we don't use very much like imipramin or protylene. But if you go towards here, you find like vanilla vaccine is very widely used. So it's peroxidine. So let's say for vanilla vaccine, if you are, so this is the drugs and here is your level of metabolism. You can be a poor metabolizer, intermediate metabolizer. This is an extensive metabolizer, which is essentially wild type. That's the most of the population. So that's what's called normal and ultra rapid metabolizer here. So let's say for vanilla vaccine, if you are a poor metabolizer, the dose needs to be cut, no, it should be 68% of what it would be if you are normal metabolizer. And if you are ultra rapid, you need to increase the dose 50% above the maximum recommended, which most people are jittery about doing without the test. So the information is there and we treat the patients. A lot of people have a lot of side effects with vanilla vaccine and they may be poor metabolizers. It's about 6% of population, of white population, Caucasian, the other six is ultra rapid. And some people don't respond and we change drugs and flip flop without maximizing the drug because they could be, if they are ultra rapid, the best procedure would be to increase the dose until they reach a level that's therapeutic meaningful for them. And here is CYP2C19. And you can see some drugs like sertraline that's too widely used. You need to cut the dose 25% if the person is a poor metabolizer. And as I said, we don't use the information at all. So that was a translational gap two. We have the information, but we stubbornly refuse to use it in clinical practice. And the gap one is the more complicated gap because it is an issue of acquiring knowledge. So this is the gap one. It's the idea to create a chip so you need to understand the pathway that the drugs would act on and then how different mutations in that or allelic variations that pathway would lead to different kinds of drug response. And then you go from the genetic information would put it in a chip and then create a chip for anti-depressant response, for example, could be anti-psychotic response as well. So another German researcher, Elizabeth Binder, did this very careful review and I did a summary review of the pharmacogenomic findings in depression. So there is a gene, the serotonin transporter that has been very widely studied. So that's like a kind of a domain into itself and there are meta-analysis and thousands of patients enrolled in those studies. And it does have an effect on the pharmacodynamics of anti-depressants. Then if you look at other genes, she broke the studies into groups of studies that had more than 2,000 patients enrolled, ends of less than 2,000, but more than 1,000 and then less than 1,000 between replication. So you can see that the data are very conflicting. So she herself, Binder, she started, she discovered this association of anti-depressant response with the FK506 finding protein five, which, of course, she puts that there as the first one because it was her own study. So there were four positive associations with that variations in that gene, but three negative associations. Some cases, like glutamate receptor, you have two positive associations and zero negative. You have another case here of the monoaminoxidase A that there were zero positive association studies and seven negative association studies. So there's pretty much a dead end here. But a lot of them you can see that there are like, you know, three studies showing a positive association for serotonin receptor 1A, five showing no association. If you add, which I did add myself manually, the number of subjects in the totality of those studies, you have more patients not responding than responding. And here, for example, you have five studies that show positive association, but the number of studies with the negative association is actually larger. So there are more people who don't appear to respond than the ones who do. I mean, in response to the genotype. So I put this kind of lightning strikes here because that's what I'm gonna talk about in the last few minutes of the presentation, which is our own work and she puts here these genes here because of what we pioneered and other people replicated. So our pharmacogenetics studies were done as part of the NIH Pharmacogenetics Research Network that was for all areas of medicine. And this is our protocol. So the idea should look at the phenotype of antidepressant response, then genotype and we went all the way over the last 10 years like from specific candidates to buy informatics approaches, NIPA identification along pathways, and then searching for new targets, including expansion data. We never did GWAS ourselves because we need very large numbers and pharmacological studies don't have the numbers of subjects that you would need for GWAS. So what we are doing right now and it's in progress as we speak, is whole genome sequencing of people who respond and not respond. And then to see if we can find something in the whole genome, which is going to be very difficult to analyze, but we have collaborators who are very good at that and with the hope of finding something. So the study consisted of collecting a DNA samples from five to 600 people, half for controls and half for patients that were treated with isofluoxetinoidezipramine. In our prospective pharmacogenetics study that had a one week single blind placebo edine followed by eight weeks of double blind drug with weekly assessments. So the first thing that the phenotype you're looking at here is the phenotype of antidepressant response. So that's a very difficult phenotype to collect and just to give you an idea, we initially to enroll the first 195 people in the study we had to assess 2,911. And here's the phenotype of antidepressant response. Our patient population was in Los Angeles. They were Mexican Americans and here's the HEMD score that decreased in over the course of the study from 20, just under 25, like 24 average, to some people being completely remitted and some people still being sick enough to enter the study. So the idea is that this variability here could be explained at least in part through genetics. So when initially we looked at specific candidates what's very interesting is that the candidate that we looked at which was CRH receptor one, nobody had studied that gene in psychiatry. And so we showed the first association in our case was the antidepressant response but now there's a whole kind of a field of research looking at it that seems to be associated with variations in this gene. In the presence of trauma in early life lead to more severe depression. So there is a whole kind of a field of study that looks at CRH receptor one variant, but we pioneered that. And the reason we went to CRH one is that the stress response seems to be very important in depression. So you have functions of the nervous system that are acutely activated during stress response that seem to be chronically activated in depression. And this issue of the selective advantage of an acute response to stress versus the chronic liability of a disease was best shown by George Cruz in this review in 2009 that it shows, for example, in acute stress response you have to conserve energy. It should not be like, you know, get hungry and go eating. So you have to conserve the energy that you have. And then if you have chronic stress, instead of something that's selective advantage, you become obese and have the metabolic syndrome. You should also conserve fluids. You should not be, you know, wasting your fluid so that then you have to go and look for water. But if you chronically stressed, you conserve fluids with hypertension. And you shouldn't be aroused and be fearful in an acute stress situation. But that chronically leads to anxiety and insomnia. And you should also be socially withdrawn. You should not be, go out and try to make a new friend when you're, you know, facing an acute predatory stress. But if you are chronically stressed, this social withdrawal is manifested as depression. So CRH is a hypothalamic peptide that's expressed in the part of ventricular nucleus of the hypothalamus and also an extra hypothalamic areas. It activates the HPA axis. And this whole axis has been shown since 1973 to be involved in the biology of depression. So that's a summary of that data. So we thought that, you know, and everybody was looking at CRH itself, but I thought, you know, if CRH's effects are mediated through the CRH receptor type one, then we should look at variations in the receptor gene. And so this our study here that was the first one looking at this gene in association with psychiatry. We showed in that protocol that I presented to you that patients who had a haplotype defined by three SNPs of the CRH receptor one, they stopped responding to antidepressants at about five weeks and were worse off if they were heterozygous than if they were homozygous for that hypotype. And this study was independent replicated with very similar results by a group in China. So that's what gives us a little bit more confidence about it. Then we had the idea, you cannot go like, you know, candidate by candidate. So we started to look at entire pathways using a bioinformatics approach to identify SNPs along the pathway. And that's very common now, but when we did it, when we first thought about it and began doing it, it was very new. So the idea is that instead of looking at the single gene, you look at an entire biological pathway and get all SNPs in that pathway. So this is the same study population. The pathway we decided to study was a, certainly if we're gonna study a pathway, let's do something a little different. So we went to the PD pathway. The PDs are phosphodiesterase enzymes that break both Psyche KMP and Psyche GMP. So depending on how much they act, you have more or less levels of Psyche KMP and GMP. And the interesting thing about them is that the drug companies have invested massively in them in that pathway and there are a number of compounds that act at that level. So potentially if there is some associations anti-depressant response, you could have a new drug already synthesized. And of course the world's best selling drug, which is individually, which is Viagra is a member of that family, but many other targets are being investigated within the phosphodiesterase pathway. So we showed that phosphodiesterase variants in the phosphodiesterase gene. So we looked at, there are 11 families of enzymes. So we looked at SNPs through the entire family. And of course, since we began to do that initial study, many more SNPs have been identified, but we did like a survey of the entire family. And we showed that a haplotype in the PD-11 was highly associated with depression and also with anti-depressant response. So given the number of comparisons, our threshold for statistical significance was right here. So we showed that these two genes were associated with depression and then also the 11A with anti-depressant response. So in depression, it's been shown that the levels of ACTH are consistently normal, but many patients are hypercoachazolimic in the presence of normal ACTH. So people have talked for a long time of a functional, like a hypertrophy of the adrenal glands that to a fixed level of ACTH, they are more responsive and make more cortisol. So just when our study was coming out, a colleague of ours from the NIH, Constantine Stratax, completely independently showed that mutations, that same gene were present in individuals with adrenocortical hyperplasia. So in conclusion to this part here, this was the first study to show potential CNS function for the PD-11 family. And our results show that if you affect PD function, particularly the cyclic-GMP-related PDs, you could have new treatment strategies for major depression. And so what we are doing now is to actually sequence entire genes, and now most recently a sequence the entire genome, but leading to that, we've been sequencing different genes that we think are relevant to anti-depressant action at different levels, from the level of metabolism of the drugs to entry into the brain to initial target binding and then to kind of a more chronic effects in brain function. So what's interesting here is that we showed that if you re-sequence genes that have been very widely studied, and again this was in our population of Mexican-Americans, we find many new variants that exceeding number, even in some cases, the number of existing variants that people knew about. So we studied eight genes in total. So the first one is BDNF, I had in that archives paper, and then this additional seven genes. We showed the Pharmacogenetic Association with the BDNF receptor, and this is the summary data slide that shows that for all seven genes that we studied in the second study, we had a total of 204 new variants, when there were 215 previously described variants, and this is the total number of variants there. So the point here is that the number of variants in the human genome is very, I think that are relevant to us, are very underestimated. And I was part, I was one of the co-investigators of the human haplotype map study, and this data that I collected from the Mexican-Americans has been used to create kind of a map of a common and rare genetic variation in diverse human populations so the Mexican-Americans are here. So this is the most diverse populations from Africa and the least diverse population, the most homogenous is the Japanese, as everybody knows. So in conclusion, I'd like to say that there are four possibilities in psychiatric genetics, conceptual possibilities, and assuming that there is a genetic problem, could be post-genetic, could be DNA methylation, could be other things, but if it is something in the sequence of the human genome, you could have genes of major effect that you saw for obesity that don't seem to be coming up for psychiatry. And I think with the amount of studies that we've been doing, so many groups in the world, I think there was some genes of major effect that would have been identified by now. Then you could have common variants of mild to moderate effect, and that's what was the big hope of GWAS initially, and those don't turn up to be so much the case or to account for most of the genetics of the disease. Then you could have common variants of very tiny effect, which could very well be the case, and if you go in that direction, you need to do GWAS of samples of 20,000, 30,000, and then you could find these tiny, tiny effects. Or you could have rare variants, which I think is more likely to be the case. And my point is that genetic variability in well-studied genes has been greatly underappreciated. There was a slide that I skipped that I showed that the repository is collected by the National Institute of Mental Health to study a genetics disease. They have very low numbers of minorities. So for example, the NIMA major repositories, for schizophrenia, they are very broadly represented, but let's say for major depression, out of 6,000 patients in the repository, 93% are white, 3% are black, zero are Asian, and zero are Latino. So if there are variants in those populations that may be relevant to those groups, they're not gonna be seen because they're not studied. The schizophrenia one is 44% white, 21% black, 20% Asian, and 14% Latino. So that's very well-balanced. But also D, for example, is 91% white, 3% black, 0% Asian. And so it's not very conducive, the kind of data sets that we have are not very conducive to find variations in ethnic minority groups. Though editing over a thousand papers per year in molecular psychiatry, common variants of mild to major effect do not appear to underlie common diseases. So my personal bet is that in psychiatry, common disease will be caused to a large degree by rare variants. And if this common disease rare allele hypothesis is true, massive re-sequencing will be required to elucidate the genomics and pharmacogenomics of depression. And as an important caveat there, future studies must include minorities. So that's the end of my presentation and these are the people who've helped us in different aspects of this research. Thank you very much.