Pharmacogenetics in Psychiatry PDF

Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... Pharmacogenetics in Psychiatry Xavier Gutierrez: Hello, everyone, and welcome to today's live broadcast, Pharmacogenetics and Psychology, presented by Dr. Daniel Mueller, head of the pharmacogenetics research clinic at the Campbell Family Mental Health Research Institute at CAMH, and associate professor in the Department of Psychiatry at the University of Toro. I am Xavier Gutierrez of Labroots, and I will be your moderator for today's event. We're delighted to bring you this educational presented by Labroots. Labroots is the leading scienti!c social networking website and producer of educational virtual events and webinars. Before we begin, I would like to remind everyone that this event is interactive. We encourage you to participate by submitting as many questions as you want at any time you want during the presentation. Just click on the ask a question box located on the far left of your screen and type the questions into the dropdown box that appear on the screen. We'll answer as many questions as we have time for at the end of the presentation. If you have trouble seeing or hearing the presentation, please click on the help desk button located in the promotion board at the bottom and or center of your screen or use the ask a question box to let us know that you're having a problem. This presentation is educational and thus o"ers continuing education credits. Please click on the continuing education credits tab located on the top right corner of the presentation window and follow the process to obtain your credits. Please join me in welcoming Dr. Mueller. I'll now turn the presentation over to him. Dr. Mueller: Hello. Thank you very much for this nice introduction. My name is Dr. Mueller. I am a sta" psychiatrist at The Center for Addiction and Mental Health in Toronto. We are Canada's largest mental health center. I'm a professor at the Department of Psychiatry and have a secondary appointment with the pharmacology and toxicology department. My area of research over the past two decades has been to improve medication treatment in psychiatry by using genetic information, which is commonly referred to as pharmacogenetics. I would like to brie#y talk about the complexities of psychiatry and perhaps also why we have di$culties in !nding the right medications and why genetics can hopefully help us to improve that considerably in 1 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... order to give the best treatment to our patients. If we look at psychiatry... Here we go. I'm trying to show you some of the common psychiatrist conditions that a psychiatrist can and will encounter typically during their work. You can see quite a number of conditions here listed by the typically... I used DSM-5 criteria. And you can see that it involves neurodevelopmental disorder, for example. Then we have all the spectrum of psychotic disorders in schizophrenia. We have bipolar disorders, depressive disorders, anxiety disorders, OCD, and many, many more. I was myself surprised, I must say. When I was in med school and when I was a student, I really believe that psychiatry is a niche area where most people will not get... will not have to deal with. And it's a rather uncommon situation, but that de!nitely is not true. People just don't talk about it so there is a lot of stigma. And those people who are really severely ill obviously are treated in hospitals and anywhere else and you just don't see them as much. However, it has been estimated that about one-third of the population, so that's one out of three will at some point in their lives encounter of psychiatric condition. And if you think about that and even if it's only 20% maybe, if you're really strict on your criteria, that means one out of !ve. And that means that basically every family has at least one someone a"ected. Every family, including second degree relatives if you wish, has at least one a"ected by statistics. So that means everyone actually in our society is likely to interact even on a family basis, but also maybe at work and anywhere else, two patients or two people who su"er from mental disorder. So it is very common actually. And that should be kept in mind because it also re#ects the high prescription rate of psychiatric medications in the community. For example, in Canada, I just saw a recent statistics where the medication which is mostly prescribed to women, number one, are antidepressants. I was very surprised to see that myself. I wouldn't believe that, but apparently that's how it is. And in certain ways, psychiatric conditions are spectrums. It's not always, again, easy to draw a line who has treatable symptoms or not. We still can do a much better job, certainly, and also understanding psychiatric conditions and de!ning them and !nding perhaps new ways of diagnostics like biomarkers and so on. But again, today, this is all about treatment. And last, not least, we also have complexities in terms of what we call personality disorders. Oops, I'm sorry. Personality disorders, which believe it or not might also often require medication treatment. Among them are things like borderline personality disorders, schizoid personality disorders and whatnot. These are milder if you wish sometimes. Sometimes they can be a bit milder 2 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... conditioned than the full disorder, but they sometimes can also be by themselves highly problematic and associated with lots of self-harm and so on. And here sometimes again, we cannot... even though these conditions are typically best treated with psychological interventions, psychotherapy, and so on, we sometimes cannot avoid using medications in order to alleviate some of the most acute symptoms. However, what are these medications about? And it's been now known for some time for decades that our brain has two major neurotransmitters. And one of those are the dopamine pathways and the other one are the serotonin pathways. And they do a lot of things, dopamine and serotonin. Sometimes we get simplistic ideas about them. Dopamine as being the pleasure hormone and serotonin being about happiness and so on. It is a bit more complex than that, but however we can certainly see that most of the medication which are prescribed particularly for psychotic disorders, which would be antipsychotics or depression and anxieties, which would be antidepressants, both of them typically target broadly either dopamine pathways or serotonin pathways. And by doing so, they often achieve... while you can often see that they achieve some good results in terms of the symptoms that patients are complaining about. However, it should be still seen as a kind of broad intervention. In physiology, when you really don't know, for example, what the germ might be, you give one of these broad antibiotics and you basically kill a bit everything and you will also hit then... Of course, you will likely hit also the germs, the bacteria that you would like to hit because they're causing the problems, but it's a little bit similar to that. So with these medications, we're still a bit bulldozing in a certain way these pathways, which again sometimes then also cause side e"ects, which we don't like and patients certainly wouldn't like at all. And you have to balance that often. You have to really balance what is the lesser evil now here. To use medications or to not use medications and how to use them and how to do this with the least side e"ects. And the good thing is newer medications are much more selective than older medications. Newer medications often are much better tolerated and also come with less side e"ects and so on. However, they still mostly target these two pathways, particularly the medication I'm going to talk about today, which are antidepressants and antipsychotics. I mostly target either or these two pathways. And that is good in a certain way that we have the medications, but again we have not been successful even though these pathways have been known for decades now. We have been at least little successful, let's say, to target psychiatric symptoms by !nding how to be perhaps more selective and perhaps even target other pathways, 3 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... which might also be important. There has been a lot of research done, unfortunately however because of the complexities of the brain, because of the heterogeneity of symptoms, and so on. We're unfortunately not there yet to o"er really advanced medications. And that's where we will then have to turn again to the shelves that we have today and see how we can do the best or treatment, how we can select and basically !nd the best treatment by the medications that we currently have. I usually start, like to start my presentations with a famous quote from William Osler, who was a Canadian physician and who was the !rst who published an encyclopedia about all medical conditions and treatments back in the 19th century. And he once said, "If it weren't for the great variability among individuals, medicine might be a science and not an art." That's a bit surprising perhaps because we all believe, of course, that our treatments are very much based on science, and on research, and on data, on evidence-based medicine, and so on. But the reality often shows that no two patients are alike. And even though they present maybe with the same symptoms, you would think they might then bene!t from the same treatment, but that is not often the case. You have to basically become a little bit creative, a little bit ready to see variations and to see one patient is improving with outside e"ects, the next patients might improve, but has side e"ects, doesn't want to take the medication. And then patients who might not even improve and have only side e"ects and then patients who nothing really happens even after six weeks of, let's say, antidepressant treatment. So here you have to become a bit creative. You have to look into sometimes into really combining perhaps medication, augmenting medications with other agents and so on. And that is complex. That is di$cult again because you never know the outcome up front. And of course it makes it a bit look like a try and error approach, even though I believe we should be careful by saying try and error all the time, but de!nitely it is a bit like you become a little bit creative and you cannot always !nd answers in the books. However, what is variation? What are it coming from? Why do people show variation? And do we know nothing about it or do we know something about it? And if we look at variability and medication outcome, we know at least a few things already, which are de!nitely important in dozing in terms of side e"ects that we might see and so on. And that is certainly age. So we would not treat a child similar to, let's say, an older adult. We know that gender matters in terms of dosing, in terms of potential side e"ects, perceived side e"ects and so on. There is also the area of sexual dysfunction here which can be important. Then there is ethnicity. That is also an interesting phenomenon, particularly in a more and more diverse world that some people from 4 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... certain ethnic groups, and I will give you examples later on in my talk, might just not tolerate medication because they have di"erent genetic variations in their drug metabolizing enzymes, for example. So that is one other reason. Another one is symptom pro!le. And what I mean by that is basically that there are many ways of how people can present when they have, for example, depression, or when they have schizophrenia. Some people in schizophrenia hallucinate more than others, some don't hallucinate at all and so on. And in depression, some people oversleep, some people have insomnia problems. So obviously if there is a such heterogeneous condition, it's hard to believe that one and the same drug will take care of everything. It certainly makes a big di"erence. Imagine also people may be getting depressed because they have been traumatized. For example, it's hard to believe that any pill will then take care of the problem as well. You might just want to know about some traumatization when you treat any patients with depression because then you would also need to tackle and start to treating traumatizations in the past. So this is an example of what I call symptom pro!le or symptom manifestation. The type and the severity of it. Then last, not least, we have drug interactions. And that's particularly important because many times if we add a drug to existing drugs or the other way around, if drugs are added to our psychiatric drugs, there can be no drug- drug interactions, but can sometimes exacerbate new symptoms, new side e"ects and so on. And so if the patient comes to see you, it's very important to also rule out any drug-drug interactions and so even with over-the-counter medications. St. John's wort has been taken by many people over-the-counter and is supposed to alleviate depression. And it does so also, but however, unfortunately it interacts with drug metabolizing enzymes, the CYP3A4 one which then can cause problems elsewhere. Mainly it basically can, for example, make other medications ine"ective. And in the UK, there has been a report that at least, believe it or not, 20 babies or so were born even though their mothers were in contraception. But by taking St. John's wort against depression, which is again, natural medicine, the contraceptives were not working any longer and therefore these mother became pregnant. So if you wish, the side e"ect here could be to have a newborn. And it's not meant ironically or something, but it tells you about the importance of also checking for doctor interactions, including over-the-counter medications. And !nally, genetic variation. We're convinced that genetic variations cannot tell us a lot also about this 5 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... variability that we do see in the response to medication. That's why we're doing this research. We as a group, as a !eld in genetic research, and it's an increasingly number of researchers, and publications, and larger projects, which are now developing and so on throughout the globe because yes, it is very promising. It's a very promising approach and can ultimately help many people and save a lot of money. Coming back to science. If you look at the publications that are out there, we can typically distinguish three types of studies. So in order to go and to take you through the studies of pharmacogenetics and psychiatry, perhaps it is important to also go through those three domains as they are typically published. And the !rst domain are the so-called drug metabolizing enzymes, where studies are conducted in genes which are known to either a"ect absorption, distribution, metabolism, or excretion of certain drugs. And those genes show variation, considerable variations at times. And so here we have a good reason also to believe that we would expect good results from such studies. Then of course there is the alternative is to look at your patients, how they respond on a certain medication and then you do a genetic test afterwards and examine which variations, which genetic variations were associated with a certain outcome, mainly improvement, and maybe which symptoms and so on. Here, the problem is a little bit that sometimes however, response to treatment remains a bit di$cult to measure starting because... already starting from the problem that people have di"erent symptoms, so they can also improve in di"erent symptoms. So you have a lot of variation here and that makes it sometimes di$cult to really do a good... have a good judgment on how e"ective drugs have been in certain areas of those others. So there can be confounders here. And therefore these studies are a bit more, if you wish, di$cult to manage and to interpret. Whereas with drug metabolizing enzymes, we can often measure drug levels very precisely that would help us, for example, to understand the impact of genetic variation. Finally, we do have a third category which are side e"ects. And here often enough, we have the chances also to be very precise in measuring the type of side e"ects. For example, weight gain induced by psychiatric medications. And therefore, this can be another independent, distinguished category to conduct studies. So that is what the !eld is about in terms of studies. And now here. This is a little bit of pharmacology, basic pharmacology. You can see left pharmacokinetics and right pharmacodynamics. And basically every time we take a pill or a drug, it goes through our intestine, it goes through our blood system and so on before it reaches the target organ, which in our case is the brain. And while it passes basically the intestines, the kidneys, the blood, 6 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... and so on, the body is typically working against elimination or cracking down, metabolizing the medication. And what's called pharmacokinetics basically. What the body does to the drug. At the target organ, in our case mostly the brain, this is called pharmacodynamics. Basically what the medication then does to the body. And we can imagine that because these are two very di"erent compartments, as a pharmacologist would say, we can imagine that we can also use these distinctions in our pharmacogenetic studies, which in fact we do. We can say already at this point of time, not as a spoiler maybe, but that pharmacokinetics has really shown to be largely determined by genetic variation, which we can at this point also measure quite well. So you're going to hear more about pharmacokinetics now because this is really where most of the studies have been conducted with most promising results. Going deeper into details or drilling it a bit further, what are these drug metabolizing enzymes? Well, there are many of them, but I think that this one, this pie chart here gives you an idea about the relevance of certain drug metabolizing enzymes. For example, you can see here on the left, CYP2D6 has a huge proportion, which means in this case, the pie chart reads like CYP2D6 is much involved in many of the psychiatric medications. If you could now imagine another pie chart in your mind, it is our only present to a minor fraction in the liver. Therefore, it can run out of capacity quite quickly if you overload, if you overwhelm your CYP2D6 system. So that's why we say it has low capacity, but it also has high a$nity, which means medications which are primarily metabolized by CYP2D6, they have to get metabolized by that enzyme. They cannot get metabolized elsewhere. And therefore we have a bottleneck situation very much with the CYP2D6. So it's a very critical gene. We will keep in mind for now. Then those other ones, CYP2C19, for example, CYP3A4 are equally important, but the situation might be a bit more di"erent here. CYP3A4 is much, much more abundant. So it's much more di$cult to, for example, cause problems here, but CYP2C19 is another example of a gene where we see much signi!cant amount of variation and also a signi!cant amount of medications being metabolized. So this gives you an idea about the enzymes we're looking at. I typically like to give you an example about case report. I like to do this because it tells you really the importance of one single enzyme and how it can really determine very critical situations or can be involved in actually life and deaths because this is unfortunately a patient back in the 1990s. He was a 36-year-old male with depression. 7 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... He eventually lost his job. He went into marital breakup and he was !rst treated with amitriptyline, but then the doctor decided to add a new medication at that time, Prozac or #uoxetine, on top of that. And six weeks later, this patient was found dead in his apartment. They measured the blood concentration of drugs and they found an excessive level from amitriptyline that was then speculated by the [inaudible 00:25:00] that would be... that would've caused the death and that this was done intentionally. And therefore the cause of death was determined as being suicide, which in depression, unfortunately, is not unusual particularly if you have further existing stressors like losing your job, losing your spouse, and so on. However, the life insurance now wouldn't pay anything. And the ex-wife therefore requested further analysis, being convinced that this ex-husband of hers would not commit suicide without even leaving a note or anything. And luckily she found someone who looked into it in details. And so press con was involved. The author of this case reports, who could in fact show that this intoxication has happened because the second medication, #uoxetine, has inhibited the CYP2D6 system. It has basically, if you wish, overwhelmed the CYP2D6 system to the point that amitriptyline, which is also metabolized by CYP2D6, could no longer be properly metabolized. And therefore it accumulated over time. And over four to six weeks, it was in fact calculated that you would reach levels which are highly toxic, which typically ended to cardiac arrest. So in this case here, because of the second drug, it was now a drug-drug interaction. It was basically an accidental overdosing when fortunately with later consequences. However, the point here is obviously that it wouldn't have been detected !rst of all if second look wouldn't have been taken, but the point is that you can see that this enzyme alone can cause a lot of issues if it's not running, or if you don't allow, or if you have anything in your system, which makes this CYP2D6 not working well. Interestingly now, there are people who are born actually about 5% or so, !ve to 10% among European patients at least, who are born with no CYP2D6 activity. So basically it is if they would take #uoxetine, [inaudible 00:27:41]. And we called them the poor metabolizers traditionally. We can also call them no metabolizers if you wish. And this is shown here in this graph. This is a graph of Andrea Gaedigk and it's important. Andrea Gaedigk is a colleague from Kansas city who has basically devoted her lifetime research to that enzyme alone. And she has brilliantly shown many times how genes can or genetic variations of that gene can in#uence expression. So by the means of the current classi!cation of metabolizer status, we have rapid metabolizers on the left, the normal metabolizers in the middle. We have slow 8 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... metabolizers with some impaired metabolizer system and then we have these poor metabolizers on the right who basically do not have any CYP2D6 activities based on genetic variations basically, genetic variations over time. You can see two things here. Basically, most people have a normal functioning CYP2D6 system. So that's good news. Most of the time, if people will get a medication, primarily metabolized CYP2D6, they will not encounter any problems. So evidence-based medicine at this point could say, well, most people do well. If we have 100 patients, at least 80% or so, 75 maybe, will do well. So evidence-based medicine is going to tell you can use this drug and just be careful, not everyone will bene!t maybe. However, the vast majority will. Now, personalized medicine and using genetic information, however, will allow us to preemptively screen for those people who might get in trouble. And that's a di"erence between, if you wish, evidence-based medicine and precision medicine because genetic variation can very nicely at this point of time distinguish and identify people who are outliers, particularly at the far left end and at the far right as in this case. And by doing so, you can avoid a lot of troubles you can imagine. I'm going to give an example of how much importance these metabolizers statuses can be, for example, in this medication here. This paroxetine is one of the !rst so-called SSRI antidepressants. Sorry. You can now see here that if you are a rapid metabolizer, if you have a system which works extremely well because you have copies actually of your CYP2D6 gene. So you have copies for whatever reason. Your body has created copies of your CYP2D6 sometime in history. And you're just inheriting it now from your parents and so on, then you can see that you can extremely e$ciently metabolize paroxetine here at the bottom. You almost do not get any therapeutic level even if you take a higher dose of paroxetine 40 milligrams. Now, the extensive metabolizer or the non-metabolizer are those in green here and they typically reach a therapeutic level at 40 milligrams. However, intermediate and poor metabolizer now can be in big problems because they will achieve much higher levels, which can be toxic for them. So if you dose someone with a CYP2D6 poor metabolizer genetic constitution, it can cause problems. They will probably have side e"ects. And this tells us the importance again about this enzyme alone. I would, however, also emphasize that there is a lot of ethnic variation for these CYP2D6 metabolizer status. So I've shown you that about !ve to 10% of the Europeans here on the right, are poor metabolizers in red, but there is about 20% of East Asians who are so called intermediate metabolizers, but what it means is they have a slightly impaired CYP2C19 system... Sorry. CYP2D6. And that means that they can basically... 9 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... they can also show more likely issues at normal doses of medications. And then interestingly in some areas in Africa, they found 40% of Africans being rapid metabolizers for 2D6 that likely has also probably had evolutionary advantages. You can imagine that CYP2D6 has not been created by nature to metabolize antidepressants, but you can well imagine that CYP2D6 has basically evolved as a way of detoxifying venoms or detoxifying anything which is toxic to your body. And if you now are more exposed to certain venoms or maybe it could be fruits or whatever, where you have toxic products having a very e$cient CYP2D6 system has probably shown to be of bene!ts. And therefore in this particular area, there has been a selective pressure towards a CYP2D6 rapid metabolizer status. And now 40% have these rapid metabolizer status and as you can imagine from the slide that I showed you before that, you will then see much less e"ects if you treat someone, for example, with paroxetine until you might know that that someone is a rapid metabolizer. You might just never get into therapeutic plasma levels. And that's very much true also. And that has been shown much of the times. And then !nally, for example, for CYP2C19, just to mention that brie#y, there is also a big di"erence between poor metabolizers, which are much, much more common in Asians than Europeans. Again, here medications with metabolized CYP2C19 will much more likely be problematic for agents, East Asians and for Europeans. Okay. This just gives you basically another idea. You see these pie charts have very di"erent colors. And what it means is this is again about the CYP2D6 system in di"erent areas, di"erent ethnic groups. And basically you can see by the... without going here too much into details, but you can see that the colors are di"erent, which means that certain genetic variations are much more likely or unlikely to occur depending on your ethnic background. So it is a complex, very complex gene because you also have to now take into consideration this variations when you interpret studies and recommendations just to keep in mind. So now what are experts saying? Expert groups who are evaluating these genes and these gene variants and medications, typically these groups, these reviews that are written on pharmacogenetic psychiatry will typically look at three things. Analytical validity, clinical validity, and clinical utility just to mention them. And analytical validity is basically really, do you have the proper tools enhanced to measure genetic variation and to understand the complexities of a gene? And yes, I guess we have a very good understanding of genes and we have very good labs who can also do that. However, we're still in research. Research is still progressing to better understand the 10 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... function of these gene variants on the gene itself and how they interact with each other. Then we have clinical validity, which basically is really kind of a gene variant be associated with a certain outcome yes or no. And that is, of course, the question we all want to know. Does it really matter if you wish? And ultimately clinical utility addresses things like, is it really ready for the clinic? Can you really now go and should you go and o"er genetic testing, for example, for everyone? Because you have other factors here involved as well. For example, economy. Is it already clear that by testing everyone who comes into your hospital, that you will at the end also save money, for example, and so on. So these are questions which are also addressed, but sometimes with varying degrees among expert groups. It's been a big pleasure over the years to work with the clinical pharmacogenomics implementation consortium, which is one of these expert groups which basically go through the whole entire feed of medicine, not just psychiatry. And are evaluating constantly which gene drug pairs are actionable, which means if there are enough research, are there enough data to pick up a gene and see how it relates to certain outcomes to any kind of drugs, but including also psychiatric drugs. And the clinical pharmacogenomics implementation consortium is independent of any, I would say, pharmaceutical companies or biotech companies or so on, and that they use criteria, quality criterias from the Institute of Medicine, which are listed here, which is basically the top standard you can have if you really want to evaluate objectively the impact of certain gene variants or pharmacogenetics in general. And so they have started to do this now for many years. And again, we've been looking at some of the most important actual dream drug pairs in psychiatry together. Here is an example of how recommendation would look like. So this is a paper that looked at the e"ects of CYP2D6 and CYP219 you've heard about on dosing of tricyclic antidepressants. So !rst generation, if you wish, of antidepressants are called tricyclics. And as you can see here on the left, you can see that the metabolizer status is listed in four categories. And on the right, you can see the level of accommodations, which was felt to be strong, which was maximum highest label you can get. So basically saying that, yes, if you do know your genetic institution, if you do know your metabolizer status, which is either one of the four, and do you do something about it or are you... are we recommending to do something about it in the clinical setting? And the recommendation was strong in three out four, which means, yes. We would highly recommend to consider that genotype constitution, that predisposition, if you want, whenever you now go and use and prescribe tricyclic antidepressants. So very convincing arguments in terms of the signs behind that recommendations. 11 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... Again, over the past years, we have published three reviews which looked at tricyclic antidepressants, again, 2D6 and 2C19. There was another one on SSRIs, which are the newer antidepressants like citalopram, widely prescribed sertraline, widely prescribed paroxetine, #uoxetine, and so on. Again with 2D6 six and 2C19. And another one, which is carbamazepine, originally developed as antiepileptic, but has been shown to also have bene!cial e"ects for bipolar disorder, for example, but also for some pain conditions. And so carbamazepine, however, can have a very, very severe side e"ect called Stevens-Johnson syndrome, which has mostly been observed with East Asians. And it has been shown that these east Asians have a certain gene variation, which is called HLA 15:02. So in some countries, in some areas in East Asia now before carbamazepine is prescribed, it is mandatory now to look at this gene variations. And that again has been reviewed by our CPIC team and you can !nd these recommendations in the publications. In progress or in consideration at this moment is atomoxetine, which is an ADHD drug. And again, CYP2D6. The classes of SNRIs, another class of antidepressants, again with CYP2D6 and CYP2C19 is being considered. And if psychotic also do have often CYP2D6 at their primary metabolizing enzyme. So it would also be interesting to look into that. And !nally, there's a gene in the blood brain barrier called ABCB one, which transports or [inaudible 00:41:20] which basically regulates the concentration of certain drugs, including antidepressants and some antipsychotics in the brain tissue. And that is another probably actual gene drug pair that should be considered too for further review and evidence-based reviewing by experts. Okay. What does the FDA say? Now, we have heard about the importance of these genes. What would the FDA, for example say? And I've listed here what the FDA would currently say, for example, for CYP2D6 poor metabolizers in antidepressants or for antidepressants on the left. And you can see that for all these drugs here, all these medications, these are all antidepressants. Also, relatively widely used to some of them where they say, "If you're not a normal metabolizer for CYP2D6, you might get into problems." You might want to adjust the dose, you might want to take something else and so on. But you can see the list is quite long. So the FDA is actually already recommending if you know your genome type, they say, basically, if you know this, then you should do something about it. They don't say you should get tested. That's not the point. They don't say where you can get tested. That's a di"erent story, but they basically tell you if you know it, you should do something about it. They list also six antipsychotics where it should be where it would matter. And a few other medications like psychostimulant moda!nil and so on where you would have strong 12 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... recommendations potentially to change your plan if you knew your genotype. Sorry. And sometimes I do say that if you are a poor metabolizer, you should really use this as a very critical clinical information. It should be basically labeled in medical reports, discharge summaries, and whatnot. Almost like as if you had an allergy, let's say, you would recommend this information to be propagated in your medical records so that future caregivers will be aware and can do something about it once you get tested. The good thing is once you get tested, once you know that you're a poor metabolizer, you know it for the rest of your life. So it's a one-time-only test you need to do in order to protect you against a lot of medication that you might encounter throughout your lifetime. So it looks like it would be a reasonable thing to know your CYP2D6 metabolizer status. And if it's not normal to actually label and #ag at any time you are prescribed any sort of medications. Someone has now done a nice job here. This is Chad Bousman's paper in Lancet Psychiatry, which is really nice to read because it has shown a little bit also what is out there in terms of opportunities to get tested, which companies would typically be around and o"er this kind of testing, but also shows that companies tend to include many genes sometimes in the tests where the evidence level is not as good as for CYP2D6 and CYP2C19, which you can see on the left bottom here even though you can see there about six, seven, or eight genes where the evidence is really strong. And then with going down, the evidence becomes lower, and lower, and lower, but companies might still feel inclined to also add those genetic tests, but all of them typically do include CYP2D6 and CYP2C19, which is shown on the right graph on the upper half. You can see that 100% of the companies all inclusive of CYP2D6 the CYP2C19 because that's really where I guess most of the evidence is out there. However, we still see a lot of things going on here in this area, in the commercialization of genetic tests. And still, however, I would very much advocate to look into solely comprehensive written reviews because unfortunately what happens is that sometimes if tests are being o"ered and they are based on where some genes are based on poor evidence, people tend to brush away the whole test and think that the whole test isn't working or is not ready yet. And this negatively a"ects the !eld of genetic testing for those genes where it would be actually really important. And as I showed you, 2D6 and 2C19 would be among of the... would be those among them and maybe HLA also for Asians. Again, we need to really encourage everyone who works in pharmacogenetics and who is making statements towards a clinical application to really choose among the good reviews. And those who are really based on science and data, again, such as CPIC 13 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... reviews or something like that in order to make proper conclusions. Okay. And last half of the talk here, basically, I'm going to tell you brie#y a little bit about of what we've been doing at CAMH here in Toronto because we have been feeling that it would actually be important to provide genetic testing to our patients. And did that starting in 2009, when really no one else, except one or two clinics such as the Mayo Clinic in the US, for example, would have started to do this genetic testing to improve treatment. We started in 2009 with a study which is listed here brie#y. And this is a #ow chart of the study. We have encouraged every patient who was treated here to be enrolled in our study and would then follow up the results of the genetic testing with them and their physicians. And would then also want to know, !rst of all, if it's a feasible thing to do, if it's accepted, if there are maybe misunderstandings potentially in terms of what these tests can do. And so we had developed a questionnaire called the PIP-FQ, which was our outcome measure here to see about... to understand outcomes and attitudes also. Just to give you an idea, later we have had the so-called impact study start in 2012 where we have also expanded our genetic testing pro!le, done more research.And we have now, through our hospitals and other hospitals and other community centers, enrolled more than 10,000 patients in the meantime. 10,000 patient genotyped where we have data on their outcome of medication, where we have data on their genetic variation and so on. So it's going to be really exciting to analyze all this data. We just have recently published the whole study protocol, if you're interested. Anyway, this is just what we're doing here in order to move forward with the implementation of that sort of genetic testing. And we have then also collaborated with a company who has used a combinatorial approach, which means that drugs are certainly targeting multiple targets and receptors, and transmitters, and whatnot. And they're metabolized also by many di"erent genes and the ultimate best test was certainly some tests where you would incorporate in an algorithm all the possible combinations of genetic variations, and then basically come up with a plan. And the plan could be, for example, to bin your medications into three categories. Yes, you can use them as directed, or you should be precautious, or you should better avoid it. But if you still want to do this, just be sure that you might do a bit more frequent monitoring for example. And just to be clear on this, no genetic testing is meant to replace common sense judgment of any physician. And even if you feel inclined to give a medication where the genetic test might warn you about, it's still ultimately at the physicians' decisions and discretion and what they want to discuss and what they feel would be best to the 14 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... patients. So it shouldn't be replacing. It's not aimed to replace any treatment algorithm or protocols that are out there. It should rather be used as additional information to optimize your treatment. This is one way of doing it. There is certainly more than this one here, but however, ultimately this is what we all want. This is what we would all be hoping to have. A tool which takes into consideration various genes and also incorporates their interactions. And for example, your CYP2D6 poor metabolizer and CYP2C19 poor metabolizer. Now, you really have probably a problem with medications much more likely, which are metabolized by these two enzymes. So you want to just know about that and you want to also know what you do in certain combinations. So that's a way to go and that's a study we're currently conducting. But I'm going to show you here now just to give you an idea, this 382 physicians who have !lled out the questionnaires about how they liked our medication. Sorry. How they like our genetic testing whenever they prescribed new medications to their patients. I'm going to show you here brie#y the results. This question was, "If you were given treatment recommendations and have taken these into consideration, would you say that compared to baseline, your patient has bene!ted from the treatment changes?" The idea was we don't want to harm. We don't want to cause harm to patients. The idea was if we do include genetic information and now patients have been treated, would we see that it might actually have caused patients to complain, for example, or physicians to say, "No. It didn't work." Also, creating perhaps false expectations was our worry here. First of all, as a physician, you always do not want to harm anyone. This is primum nihil nocere. And the results were surprising in certain ways that we can see that basically these are the outcomes. Anytime we give genetic information and patients were assessed for a second time or for a third time later on by the same physician, most likely was a predominance of under 20 to two times patients improved and no one or actually only two reported to get minimally worse. Obviously, this is great because it tells there was apparently no harm done, which was our !rst goal, to understand what happens if you use pharmacogenetics testing. Now, is it a proof that pharmacogenetics is superior to treatment as usual? No. That's not the proof here, but at least it shows again that you're unlikely to harm anyone in this situation. And this is what I'm saying here so far, so good. But however, we would need a di"erent sort of study to evaluate the superiority of treatment. And that's where we started our RCT, randomized controlled trial, which is called the GAPP study. And this is an ongoing study where we are having patients with depression, patients with schizophrenia. They are prospectively assessed once we have genetic testing completed and give them the recommendations to physicians and once where the 15 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... physicians could just choose and were blind to the genotypes, which we call treatment as usual. And that will be compared after 12 weeks of treatment and long-term follow ups are also included, cost-bene!t analysis will be added, and so on. And this should also then hopefully show us the superiority and to which extent genetic-driven treatment is better than treatment as usual. We have then also included markers for antipsychotic-induced weight gain that we have developed here in Toronto, that we have identi!ed here in Toronto, I should say. And also we want to know whether or not using these markers for antipsychotic- induced weight gain can also be bene!cial in treatment upfront. Good. So with that, I conclude the !rst large part of pharmacokinetics. And we'll use the last minutes to brie#y take you through the two other remaining domains. One of which is symptom reduction, therapeutic response, as we've said. And here we have recently, more recently started to conduct some research in late life depression. This is characterized by depression after age of 60, 65 typically. And this is another somewhat challenging condition to treat sometimes because there are more comorbidities now in the elderly, more comedications. They're more susceptible to side e"ects many times. So here, we also believe that if we could improve treatment by using genetics, we can largely expect bene!ts. And also it should be noted that depression is a risk factor for Alzheimer's disease. And therefore treating repression adequately, and appropriately, and e$ciently will also delay or even prevent perhaps onset of Alzheimer in many patients. So that is the breakdown of the study. It's a very, very nice study sample. 350 subjects were treated !rst 12 weeks with venlafaxine. And it was related to a bit afterwards if there are responders or not. And if there were not responders, they have moved on to placebo or [inaudible 00:56:36] fragmentation. But the point is here that we clearly had a very good understanding if these patients were responding on venlafaxine or not. So here is a breakdown of the response curves. And you can clearly see that the blue line means on average patients, this group of patients, this cluster of patients has not responded very well. Has mostly remained more or less in the same symptom severity score. And you can see two other clusters I would say. Even though you can almost group them, but which have shown either faster response at the beginning, but then less sustained progress later on or people who have !rst not shown much improvement in the !rst one of the weeks, but then had a sustained and actually optimal way of responding and alleviating the symptoms. Now, we looked at a very obvious candidate, which is the norepinephrine transporter gene because the norepinephrine transporter gene, the enzyme is blocked by this 16 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... medication. Venlafaxine is blocking norepinephrine transport within the synaptic cleft. And we could nicely see that death variation was nicely associated with outcome to treatment. And if you look at the orange line, these are those people who have responded much better through venlafaxine and they had a genotype which actually a"ected the expression of the norepinephrine transporter. And that is a nice study. I think a nice evidence that also suggest of evidence until for the replicated perhaps that this gene might play a role in late life depression if you treat patients with an SNRI. And that can be used hopefully in the future to... and added in genetic testing modules to improve treatment. Last, not least now, the last minutes is going to be side e"ects. I've been particularly involved in studying weight gain because weight gain is a very severe... can be a very severe side e"ects with particularly two antipsychotic medications, which are listed here on the left, clozapine and olanzapine because on average on adults after 12 weeks, four to !ve kilograms of weight. And that is a substantial amount. And keep in mind that some people might not gain weight perhaps even, but some people now gain probably even double or triple the amount of weight in this time. So there's a huge variation. And unfortunately, however, why don't we just then pick lowest risk medications? And it's being done. This is why aripiprazole on the right here is one of the most prescribed antipsychotics at this moment because it has much lower propensity to induce weight gain and is otherwise well tolerated also. Unfortunately when conditions are more severe, more chronic, and treatment resistant, clozapine remains still the antipsychotic, the state of art for treatment resistant schizophrenia. So the problem is we just cannot avoid using it. And probably 10% of patients on schizophrenia are taking clozapine and are bene!ting tremendously about this. Unfortunately, however, some of them gain a lot of weight and would like to understand more about the mechanism and to avoid it. So we've done a series of studies in the past. We've looked at various gene pathways, and this is just a list of genes we found... list of genes where we found an interesting association with antipsychotic-induced weight gain to be followed up and also to be evaluated. But there's one gene here, which I believe is particularly interesting and that's a melanocortin-4 receptor gene. Melanocortin-4 receptor is involved in satiety and appetite regulation. There is a gene variant, which was also [inaudible 01:00:41] obesity in the general population. And it looks like that same variant or at least a variant, which is in linkage to equilibrium, which is closed by and does also a"ect gene expression, if you wish, is 17 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... very much involved in risk for weight gain, which you can see here on these four samples. And each time in each of these four samples across the world, it was shown that they also have this [inaudible 01:01:11] genotype are at much higher risk to signi!cantly gain weight. And that certainly is a good study result because you see the replications in di"erent areas with di"erent medications in di"erent patients. And hopefully this gene can be further validated and then included in a risk, in a genetic risk panel like this one here, which is again a very preliminary study, but based on our study sample if we included the six genes into one panel and we would test all these six genes preemptively before getting treatment, we could nicely distinguish people who have low risk genes or low risk gene variants. They would even on average, tend to lose some weight, but those who have more, at least two, or three, or four risk variants would gain weight and also have !ve, six, or seven of these gene variants. They would actually gain a lot of weight at least 10% or more. So that's where we are hoping to go to building a multigene test also for side e"ects, which can be used independently of any of the other tests, for example, the CYP2D6 test and so on or in conjunction at some point, but this is hopefully what we're going to. So last, not least then, I would like to summarize. I guess you've all seen and understood the current situation for the so-called phase one CYP enzymes and how much they in#uence drug levels response and side e"ects with many psychotropic antidepressant antipsychotics. You've been shown that... or I guess you get an understanding that implementation is slowly progressing and it's more and more adopted globally. Genetic tests might become available. However, also speci!cally to predict side e"ects. Excuse me. And this is the group here in Toronto I'm almost closely working with. I would like to thank them because obviously it's a lot of work here being done and we're basically having a great team here and a great infrastructure to do many of these science research tests, but also in terms of clinical application and implementation. So with that, I would like to stop my presentation. Thank you so much for your attention. And please let me know if you have any questions. Thank you. Xavier Gutierrez: Thank you, Dr. Mueller, for that informative presentation. We will now start the live Q&A portion of the webinar. If you have a question you'd like to ask, please do so now. Just click on the ask a question dropdown box located on the far left of your presentation window. Type your question into the box that appears on your screen and click the send button. We'll answer as many of your questions as we have time for. Okay. Let's get started. Our !rst question is, do you think PGx is ready for clinical application? 18 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... Dr. Mueller: Yeah. PGx is abbreviation for pharmacogenetics. And as you can see or as you have heard, it is now recommended to use whenever you know your genotype information and you are now expected to be treated with medications, which means once you know them means obviously once you have undergone some way of genetic testing. The question really is, would you like to do it? Would you not like to know it, your genotypes? And here we see that the majority of patients is clearly in favor of conducting genetic testing whenever they know that they need to take a medication. The question really remains, however, who's going to pay for this and how is information delivered? And I believe that coming to conclude it, I would think that yes, it is ready for clinical application as long as you do it properly, as long as you have access to a good lab, and as long as you can certainly also cover the cost somewhere. Then it shouldn't be a problem. Now, if you want to, however, be on the more, let's say, reasonable economical side, you can now decide to, for example, give !rst everyone a chance to respond on a standard antidepressant, which might be safe to prescribe, for example, sertraline, because it does not... it is not so much metabolized by these two drug enzymes, but if it doesn't work out and you now have to give a second medication in maybe half of your patients that you treated, then a genetic test should much more be considered at this point of time because now you want to really probably look into more details and also would bene!t from our information. Xavier Gutierrez: Okay. Where should people get tested? Dr. Mueller: Yeah. That's an excellent question. Basically, it really very much depends on which clinic you might be going to. Do they already o"er genetic testing. And there are more and more clinics who do so, but perhaps before you get into treatment, you may want to !nd out whether or not there is a clinic in your city, which does provide genetic testing as part of your treatment plan. You may want otherwise look up the internet. You may want to perhaps also have a discussion with your insurance company if they would reimburse that because some insurance companies do reimburse testing and they might have collaborations with certain partners, and then you could follow their advices and certainly, you are free to meet with your physician and discuss it with them and they might know ways of how and where to do it. Ultimately you can also collaborate with a physician and you can also suggest them to help you get the genetic testing done because in many times, companies will like to have and report results to a physician rather than to patients directly. And therefore, you should perhaps speak to a physician and see what they know, you should do some research, !nd clinics in your city, talk to insurance 19 of 20 6/26/24, 7:56 PM Pharmacogenetics in Psychiatry Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... companies, and so on. You should be able to !nd a good plan. And again, there is research publications who also list centers. Otherwise, feel free to connect with researcher like me. We're happy to assist and hopefully can !nd some ways of... where you could ideally !nd your genetic testing lab. Xavier Gutierrez: Okay. And we have time for one more question. What genes should they look at? Dr. Mueller: Another excellent question. And I think that we have heard in my talk here that at this point of time, if you really go by conservative means, if you really follow science and research data, there is two enzymes for drug metabolizing purposes. You want to know for sure this is 2D6 and 2C19, then you might want to consider HLA in case you have... in case you might be an Asian and you are potentially looking into [inaudible 01:09:54] treatment. These are I would think are the most conservative standards of the genes you should absolutely look at. And at this point of time, the best evidence is for these two genes with psychiatric medications. The other ones are not necessarily useless. Other ones can include other enzymes and so on. But again, the level is lower and the information, the actionable information might be just less and might be more basically a bit more experimental at this point of time, but it is important, of course, to conduct research and to also !nd the right balance between a standardized treatment where you have a good evidence plus combining it with genes which are still more under investigation in order to allow also for more research and for a better understanding for that in the future. We can expand the gene lists much more and with much better con!dence and much better evidence. Yeah. Xavier Gutierrez: All right. I would like to once again thank Dr. Mueller for his presentation. I would also like to thank Labroots for making today's educational webcast possible. Before we go, I want to let everyone know that today's broadcast will be available on demand viewing through September of 2018. You will receive an email from Labroots letting you know when this webcast will be available for replay. Please share that announcement with your colleagues who may have missed today's live event. That's all for now. Thank you for joining us. We hope to see you again soon. Goodbye. Print this page 20 of 20 6/26/24, 7:56 PM Pharmacology: Drug Binding Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... Pharmacology: Drug Binding Most drugs act on a cellular level by chemically binding to receptors on cell membranes or inside cells. The cell membrane contains receptors for many kinds of substances, such as hormones and neurotransmitters. Some receptors also interact with drug molecules. As a drug molecule binds to a receptor, reactions are initiated that stimulate or inhibit regular cellular functions. One type of reaction activates, deactivates, or otherwise alters intercellular enzymes. Almost all cellular functions are catalyzed by enzymes. Therefore, drug-induced alterations can greatly increase or decrease the rate of cellular metabolism. Another type of reaction involves changes in the permeability of cell membranes. A drug molecule binds to an ion channel receptor, a receptor protein that is a structural component of the cell membrane. The drug's binding may open or close the ion channels to allow or prohibit the movement of ions into the cell. In nerve cells, for example, movement of sodium ions into the cell usually excites the cell. Movement of potassium ions out of the nerve cell inhibits nerve cell excitability and function. Print this page 1 of 1 6/26/24, 7:56 PM 2-minute Neuroscience: Synaptic Transmission Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... 2-minute Neuroscience: Synaptic Transmission Welcome to 2-Minute Neuroscience, where I simplistically explain neuroscience topics in two minutes or less. In this installment, I will discuss synaptic transmission. Most communication between neurons occurs at a specialized structure called a synapse. The synapse is an area where two neurons come close enough to one another, that they are able to pass chemical signals from one cell to another. The neurons are not actually connected, but are separated by a microscopically small space called the synaptic cleft. The cleft is less than 40 nanometers wide. By comparison, a human hair is about 75,000 nanometers wide. The neuron where the signal is initiated is called the pre-synaptic neuron, while the neuron that receives the signal is called the post-synaptic neuron. In the pre-synaptic neuron there are chemical signals called neurotransmitters that are packaged into small sacks called vesicles. Each vesicle can contain thousands of neurotransmitter molecules. When the pre-synaptic neuron is excited by an electrical signal called an action potential, this causes the vesicles to fuse with the pre-synaptic membrane and release their contents into the synaptic cleft. Once they're in the synaptic cleft, neurotransmitters interact with receptors on the posts-synaptic membrane. They bind to these receptors and can cause an action to occur in the posts- synaptic cell as a result. This action may involve increasing the likelihood that the post- synaptic cell will become activated in !re an action potential or decreasing it. Eventually the neurotransmitter molecules must be cleared from the synaptic left. Some of them will simply drift away in a process called di"usion. In some cases, the neurotransmitter is taken back up into the pre-synaptic neuron in a process called re- uptake. Once back inside the pre-synaptic neuron, the neurotransmitter can be recycled and reused. In other cases, enzymes break down the neurotransmitter within the synaptic cleft. Then the component parts of the neurotransmitter can be sent back into the pre-synaptic neuron to make more neurotransmitter. Print this page 1 of 1 6/26/24, 7:56 PM Synaptic Transmission and Neural Pathways of Psychopharmacology T... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... Synaptic Transmission and Neural Pathways of Psychopharmacology Sally Miller: Well, listen. Thank you so much for coming back for slide set number two. I didn't bother with the video this time because I really look pretty much the same as I did last time. And that's not the primary purpose of our conversation here. So forgive me for staying o! camera now. But o! camera is really where I'd rather be. Anyway, now I want to talk a little bit about some of the physiology more speci"c to psychopharmacology, and that begins with a review of synaptic transmission and neural pathways. Now, again, somewhere in your past maybe in some physiology course or who knows, way back when an undergrad or even if you had a true physiology course as part of your graduate education, you probably talked about the process of synaptic transmission very generically because it is the way that cells communicate with each other. They communicate via synapse. But we want to look at it with a little bit more detail, a bit more of a critical eye here in the world of psychopharmacology because that really is what we are impacting with virtually every single medication we prescribe. I'm trying to think of one. As I sit here saying this, I'm trying to think of one medication in the mental health world that doesn't involve synaptic transmission or does not manipulate synaptic transmission. And I'm sure that it exists somewhere. But I can't think of one o! the top of my head. So su#ce it to say that the overwhelming majority of things that you prescribe for people to help control mental health symptoms and disease will in some way alter a dysfunctional synaptic transmission. The other thing we need to look at here are relevant neural pathways because in the world of mental health and mental health symptoms, the things that-- these are the two things that matter. We have synapses and we're interested primarily in chemical synapses. We have synapses where one nerve cell in the central nervous system communicates with another nerve cell in the central nervous system by way of a chemical synapse. A chemical neurotransmitter communicates between two nerve cells. And when that communication is dysfunctional in some way, that's what produces an imbalance 1 of 27 6/26/24, 7:55 PM Synaptic Transmission and Neural Pathways of Psychopharmacology T... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... leading to symptoms. In which neural pathway that happens is in part what determines what kind of symptoms and ultimately what kind of diagnosis the patient has. So we look at the chemical transmitters in synaptic transmission and the neural pathways in which dysregulation occurs. And that's how we get to our diagnoses. And that's how we get to our treatment targets. So synaptic transmission and neural pathways, they're the two things of interest for this next 45 minutes or so. All right. So the synapse. Remember that in very basic terms synaptic transmission is the mechanism by which two cells communicate with each other. When we talk about a synapse, we have a presynaptic neuron, a postsynaptic neuron, a synaptic cleft, which is the extracellular space between the two and then the entire thing is a synapse. So what we're looking at here is a synapse up close and personal. So here's my laser pointer again. The whole thing is the synapse. And please forgive me if I'm being-- if I sound like I'm being pedantic and telling you things you already know. It's again because I want these concepts to just be second nature. I want them to be so intuitive that you don't even have to stop and think about them consciously. So if it's a review for you, great. We always learn best when we hear things in more than one way. And if it's the "rst time you're really paying attention to it, well, don't worry, we'll probably talk about it again. So anyway back to our synapse. We've got the entire thing here as a synapse. The synapse is comprised of the presynaptic neuron or the nerve cell that's going to deliver a chemical transmitter. We have the postsynaptic neuron and this represents the postsynaptic neuronal membrane. This is the cell membrane that will have receptors embedded in it to which the chemical transmitter released from the presynaptic neuron will bind. So we have the presynaptic neuron that delivers a message by way of transmitter. We have a postsynaptic neuron where the membranes proteins are embedded or the receptor proteins is what I'm trying to say are embedded. The area between the two-- the extracellular space in between them is referred to as the synaptic cleft and the entire thing is referred to as the synapse. And in very gross terms this is what you see going on here. The presynaptic neuron contains a chemical transmitter. Something has come along to cause release of that transmitter. The transmitter binds to receptors in the postsynaptic neuron and then 2 of 27 6/26/24, 7:55 PM Synaptic Transmission and Neural Pathways of Psychopharmacology T... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... some response or some e!ect occurs. This is what's going wrong in most mental health symptoms and this is what we're going to target with drug therapy. And so that's the gross picture. Let's look at it in a little bit more detail now. Remember that you do want to understand the basic structure and function of the neuron, neuronal discharge, and very importantly, the chemical neurotransmitters because that is the basis of nervous system and mental health pathophysiology. The transmitters, the chemical neurotransmitters are the mechanism by which a message or an impulse travels from one neuron to the other through these relevant neural pathways and ultimately out into the periphery. But, of course, our interest right now is the central nervous system. So that's like the overview. OK. So here we go a little bit more up close and personal. What you've got is your presynaptic neuron, which is tan or beige or whatever color you think that is, a little bit of yellow there. So the presynaptic neuron is comprised of the cell body, which is where all the real stu! happens. That's where the nucleus is, the organelles, the endoplasmic reticulum, and the Golgi apparatus, and the lysosomes, and all like all this stu! goes on in the cell body. Protruding from the cell body, you see these things that look like tree branches or antenna, antenna really is what they are. These are dendrites. And these dendrites truly are receivers. They are part of the cell. They are surrounded by a cell membrane and they contain a bunch of receptors. And these the receptors embedded in these antenna looking things are forever being stimulated by the environment. The receptors may be bound by chemicals coming from other neurons that are not pictured here. There are receptors that might be activated by alterations in pH, by alterations in electrolyte content or other ions, changes in temperature, medications that are administered. So all things may extubate the various receptors that are embedded in these dendrites. The messages that are transmitted by way of activation of these receptors are conducted down to the cell body. This is unipolar. This moves in one direction. These are your antenna. They process all the signals. The signals are transmitted to the cell body. And the cell body ultimately balances the impact of these signals. Some signals are excitatory, some are inhibitory. And what I mean by that is that the excitatory signals will cause a rise in the membrane voltage. 3 of 27 6/26/24, 7:55 PM Synaptic Transmission and Neural Pathways of Psychopharmacology T... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... Again, I need to ask you to hearken back to your more basic physiology course. Remember that all cell membranes hold a charge like a capacitor. They hold a charge and that charge is created by the movement of electrolytes charged particles across the cell membrane. So every cell membrane has an inherent charge. Even in the resting state we refer to that as a resting potential. And then based on all of the signals that are received by these dendrites, that charge will either rise, the voltage will go up, or the voltage will go down. Consider that in most neurons. The resting membrane potential, the membrane potential or the charge inside the cell membrane in the resting state is somewhere around minus 60 millivolts. So that's at rest. The cell is not doing anything. Depending on the messages that are picked up by these dendrites, some of these messages will excite the cell body, meaning it raises the voltage. So minus 60 minus 50 minus 40. Other stimuli will inhibit or actually hyperpolarize the cell meaning drop the voltage. So some stimuli might make it go from minus 60 minus 70 minus 80. So you can see you got a bunch of antenna here you're picking up a bunch of di!erent signals, some of them are excitatory, meaning it would drive the voltage up. Others are inhibitory, meaning it would drive the voltage down. The cell body processes all of these stimuli. And if the net e!ect is that the voltage rises above a certain threshold, then we will have an action potential or this neuron will discharge. It will reach threshold, it will act. And once this starts, it can't be stopped. An action potential occurs meaning that the rise in voltage is conducted along a specialized area of the neuron referred to as the axon. Remember, the axon is covered in white matter referred to as a myelin sheath. And it's like an insulator. And that white matter has notches. So what I want. I swear I'm having a TIA. Forgive me for this. Notches at regular intervals, that's what I'm trying to say. And so when the voltage goes up, this electrical impulse goes shooting down this axon. It moves along the insulation. It moves along the white matter very quickly jumping from notch to notch to notch. This allows for an orderly systematic conduction of this voltage. And this voltage goes all the way down to the very ends of the presynaptic neuron to these specialized areas called axon terminals. I know the whole thing's not labeled, but this was the best picture I could get my hands on copyright free. 4 of 27 6/26/24, 7:55 PM Synaptic Transmission and Neural Pathways of Psychopharmacology T... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... So this voltage shoots all the way down to the very end of this presynaptic neuron. This is referred to as the axon terminal. See here it's lit up because it's electri"ed. This is the thing that we were looking at a couple slides ago that looks like a purple golf club head. This is the thing that has all of the chemical transmitter in it. And when this cell receives enough excitatory stimuli that the net e!ect is the voltage rises to threshold, an action potential occurs, that voltage shoots down the axon all the way down to the axon terminal, and that causes those vesicles containing neurotransmitter to bind to the inner surface of the cell membrane here and then be spilled out into that synaptic cleft. That chemical transmitter will then bind to receptors on the postsynaptic neuron, which is featured here in blue and a!ect some sort of response in the postsynaptic neuron. This chemical might be inhibitory and cause the voltage to go down. This chemical might be excitatory and cause the voltage to go up. It doesn't matter. Whatever it does, this chemicals message will be processed with all the other messages received by this dendrite and then this neuron will either reach threshold or not. And so the message will either perpetuate or it will not. But that's the process we're talking about here. This is what synaptic transmission is. When any given neuron processes all of its excitatory and inhibitory stimuli, if the net e!ect is that excitation occurs so that the voltage rises above a certain threshold, the cell will discharge and action potential occurs, the electricity moves smoothly down this myelin sheath all the way down to the axon terminal. Chemical transmitter is released and binds to receptors on the postsynaptic neuron. This is what's wrong in mental health diagnoses and symptoms. And this is what we're going to try to impact. Either there's too much neurotransmitter or not enough neurotransmitter, and that's what produces symptoms. And what kind of symptoms you have depends upon which neurotransmitter is dysregulated in which neural pathway. And so that's it. I mean I'm sure everything I just said is written out here in narrative text. So if you want to read about it again, again, and again, it's right here. But this just says what I just said. So I don't think I have to repeat every word. The only thing I would mention here is that there are a couple of di!erent types of synapses. Synapse just means the area in which two cells communicate. We have chemical synapses and we have electrical synapses. 5 of 27 6/26/24, 7:55 PM Synaptic Transmission and Neural Pathways of Psychopharmacology T... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... Electrical synapses don't require a chemical transmitter. Electrical synapses are when the two cell membranes actually touch. So the change in voltage is immediately conferred from one to the other and a chemical is not required. And there are issues with that too in mental health. And in fact, this is the basis of things like electroconvulsive therapy and transcranial magnetic therapy. So we de"nitely do have therapeutic measures that impact electrical synapses. But that's not what we're talking about with drug therapy. With drug therapy, we're talking about chemical synapses. So that's the focus of our conversation here. And here's just another up close and personal view. Same thing di!erent perspective. Let's see where it's my laser pointer. All right. So here's your presynaptic neuron. This is that little thing that was-- look like a tiny little triangle at the end of the presynaptic neuron on the last picture slide, the one that was all lit up like a little star. And so this is where the action happens. The chemical transmitter is stored in vesicles when the cell body up here has reached threshold when there's enough excitation to discharge an action potential like a little lightning bolt. That action potential comes all the way down here, produces a fusion of these chemical containing vesicles to the inner surface of the membrane. Chemical spills out. Chemical binds to receptors on the postsynaptic membrane. And then depending on what this chemical is, it will either cause a lowering of the voltage in this postsynaptic membrane or an increase. And that's what we're talking about here. So chemical synapses may be either excitatory or inhibitory. I alluded to this a few minutes ago. Excitatory synapses are those synapses in which release of chemical transmitter and binding to the postsynaptic neuron raises the voltage and increases the probability that an action potential will occur in the postsynaptic cell. Inhibitory synapses are those where the chemical transmitter causes a response in the postsynaptic neuron that lowers the voltage of that postsynaptic neuron, and so obviously inhibits the likelihood that an action potential will occur in the postsynaptic neuron. And not only are some synapses excitatory and some are inhibitory, but certain neurotransmitters can be excitatory or inhibitory depending upon which neural pathway we're looking at. So it's not all that straightforward just because I mean it is, but it's easy to get mixed up if you don't really understand the process. So well, let's go to the next slide for now. Sometimes I get excited and get ahead of myself as you probably "gured out in the last slide set. So I'll try to be more-- I'll try to 6 of 27 6/26/24, 7:55 PM Synaptic Transmission and Neural Pathways of Psychopharmacology T... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... behave and stay on task with my slide. So the process of synaptic transmission includes four steps. And we want to look at those steps speci"cally because those are going to be our treatment target when we give people meds. So I know I've said this a few times over, but again, I want this all to just be intuitive. I want you to not even have to consciously think about this when we start giving people medications. So here are the four steps of synaptic transmission. First is release of a chemical transmitter from the presynaptic neuron or the presynaptic nerve terminal/axon terminal. You know how in science we have to have four words for everything-- every one thing so that it's confusing. So I've used the word axon terminal interchangeably with nerve terminal. What I'm talking about there is the very end of the presynaptic neuron where chemical transmitter is released. That's the "rst step. Then that chemical has to di!use to the postsynaptic membrane. Remember, di!usion is-- this is a physiologic law. Fick's "rst law of di!usion is that solutes will move from an area of high concentration to an area of low concentration. So we have a scienti"c foundation for making the assumption that chemical transmitters will di!use away from the presynaptic neuron toward the postsynaptic neuron. The third step is binding of the transmitter to the postsynaptic receptor which produces a conductance increase in the postsynaptic membrane. That binding of chemical to the postsynaptic receptor is going to do something. It's going to open some channel and facilitate movement of some charged particle which is what creates the change in voltage that either will be excitatory or inhibitory. And then the last step is inactivation of the transmitter. This is the one we really haven't talked about so much. I know the "rst three, I've already managed to "nd like "ve di!erent ways to talk about them in the "rst 15 minutes of this slide set. But inactivation of the transmitter we haven't really talked about. And it is important because you can't have the transmitter hanging around forever or else you'll have the reaction hanging around forever. You'll have the postsynaptic neuron perpetually stimulated which is usually not a good thing. Perpetual stimulation is never a good thing. In all phases of life, stimulation should be measured and proportional and appropriate. And when it's time for it to be done, it needs to be done so that chemical transmitter-- we have to get rid of it in some way. 7 of 27 6/26/24, 7:55 PM Synaptic Transmission and Neural Pathways of Psychopharmacology T... https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425007-dt-... We have to "nd some way once it has served its purpose to get rid of it. It is a process. It is de"nitely one that we target with medication, and it's the fourth step of synaptic transmission. So release of transmitter, di!usion, binding to the postsynaptic membrane and inactivation. Those were the four distinct processes. So by way of example, let's talk about dopamine for a minute. Dopamine is a neurotransmitter that does feature prominently in psychotic disorders. I don't know if I've said it to you, probably not because this is only the second slide set. The "rst one where we're really talking about anything speci"c to the brain. I teach this stu! so much and lecture on it in so many di!erent places that sometimes I may think I've said it to you and it was somebody else. So I'm going to try not to do that. Anyway, when we talk about mental health symptoms and mental health disorders, it's really just a handful of neurotransmitter

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