Cases welco transcript — SMP305 lecture transcript

Yeah. Right, great, so can you guys all hear me OK? Um, sorry about the slow start, um. It's the middle of the summer, so perhaps we can just be relaxed. Uh, so my name's Will Gann. I'm a consultant psychiatrist, um, here at Sheffield, um. And I've been delivering this psychopharmacology teaching for a few years now. Um, it's going to be in two halves. Um, we will focus in the first half on antidepressants, um, and then in the second half we'll, we'll think about antipsychotics. I, I suppose importantly um you guys will need to go and do some of your own studying as well, um, because we won't be covering um a few kind of big topics. I think the the most important thing for you to go and read about is, uh, mood stabilisers, um, and in particular lithium, uh, cos we didn't have time to include that in the, the teaching, um. We will cover cognitive enhancers with some of my older adult psychiatry colleagues, um, and you you will have some another lecture on drugs of abuse as well. Um, so we're we're choosing to focus today on, on, on the two main topics of antidepressants and antipsychotics. So in terms of antidepressants, um, I'm gonna kind of take you through the timeline of drug discovery for an antidepressants, um, and, and use that as a, as a way of uh kind of thinking about them, but um, I, I, I, I suppose I'm I'm aiming this, this whole talk at um at at GPs of the future. So, um, I would expect you guys to be able to initiate antidepressants in general practise, um. So you should be prepared to do an Oski scenario, for example, counselling a patient on the side effects, the potential benefits and risks of using an antidepressant. And then for the second half of the talk when we're talking about antipsychotics, I'll be focusing more on your review and the long-term monitoring of antipsychotics. But we're gonna talk about uh different classes of antidepressant, we're gonna talk about side effects um and then kind of um some frequently asked questions about prescribing um. So, um, this apparently is somewhere fairly local to us, this is where, uh, the story of antidepressants began, um, so, um. Back in the day, if somebody had TB and we didn't have curative treatment for TB, um we would just kind of lock them away in asylums, and this was one of the TB treatment asylums, yeah, somewhere, somewhere nearby. And in the early 1950s when the first anti-tuberculous drugs came onto the market, a group of, Infectious diseases specialists noticed that if they gave iproniazide to Their patients would experience an elevation of their mood that couldn't be explained by better treatment of their TB and this was the first antidepressant, iproniazide, and it's still in the BNF as a treatment for TB. And the reason why iproniazide is an antidepressant is because it blocks the monoamine oxidase enzyme. Which on this schematic is the um is that uh uh that enzyme on the right hand side. um and you you you don't need to get into the into the details of um of of the different types of monoamine oxidase, um but um the purpose of this enzyme is to mop up the synaptic cleft um of all of the neurotransmitters that were released and ready for the next action potential. Um, and you've got loads of, um, monoamine oxidase in your brain, but you've also got loads of it in your gut, um. Uh, so, um, if you, um, it's involved in, in, in the metabolism of, of, of various things, but, um. One of the things that is involved in metabolising is tyramine, which is found in lots of foods but particularly Particularly fermented produce, so cheese, beer, wine, uh, preserved meats, that sort of thing. Um, and if you, if somebody has been using a monoamine oxidase inhibitor, um, and they consume tyramine rich food, then they can have a serious um kind of drug interaction effect where they get headaches, um, blood pressure disturbance, it can be dangerous, um. So this limits the clinical utility of monoamine oxidase inhibitors. The reason why I've started off kind of telling you this story though is that it kind of shows how drug discovery works in psychiatry or has worked in psychiatry so far in that we serendipitously find that a that a molecule has has an effect on a psychiatric condition and we then look post hoc on how it's working in the brain. And we know that the reason why monoamine oxidase inhibitors work in the brain is that they block that degradation enzyme, which means that there's increased neurotransmitter in the synaptic cleft, and that has the effects on mood and we'll unpack why that might be a bit later on in this half. Later on in the 1950s, um, we discovered imipramine, which was the first um tricyclic antidepressant, um, and like the monoamine oxidase inhibitors, um, that also increases um the concentration of serotonin and noradrenaline at the synaptic cleft, but it does does so through a different mechanism. It blocks the reuptake transporter in the pre-synaptic cell. And that means that it doesn't have that um that tyramine reaction, the cheese reaction that the monoamine oxidase inhibitors have. But unfortunately it does have some side effects, so tricyclic medications generally have quite significant anticholinergic side effects, so. You guys will know that there's a big push to try and reduce anticholinergic burden, um, across, um, well, all of our patients really, because a lot of drugs have got unwanted anticholinergic effect. Um, and if you've got too great an anticholinergic burden for a long period of time in your life, you do increase your risk of dementia. In later life, but also causes difficulties, you know, passing urine, accommodating, um, you know, having a dry mouth and constipation as well. It can also cause disturbed blood pressure through their action on alpha-1 receptors and can also cause weight gain and sedation as a result of antihistaminergic effect, but fairly significantly, they're also dangerous in overdose, which is a big problem for a psychiatric medication because our patients sometimes do take overdoses. Um, And then later on in the 1980s, um we had um the SSRI's come to market, um, and these were um major um blockbuster uh medications for uh the companies that brought them to market. Um they also work um by blocking the uh the serotonin reuptake, um, transporter. But they don't have as many of the unwanted side effects of tricyclics, and that really was the innovation that changed the field. It wasn't about efficacy or any kind of novel mechanism of action. It was actually about the lack of unwanted side effects. And we now have evidence that SSRIs are useful for a lot of different treatments in psychiatry, including depression, generalised anxiety disorder, PTSD, eating disorders, particularly bulimia, and obsessive compulsive disorder. And we have got a couple of additional medications as well, so we've got mirtazapine, which is kind of more of a serotonin receptor modulator rather than rather than having SSRI effects. Venlafaxine and duloxetine are both SNRIs, so they they block the serotonin reuptake transporter but also the noradrenaline reuptake inhibitor. Duuloxetine has some additional evidence as a treatment for chronic pain, so in general practise you might consider duloxetine as a treatment if your patient's also got comorbid chronic pain difficulties. So what about the side effects of SSRI's? Um, well, classically, most people will describe some nausea. GI upset. The most amount of serotonin in your body is found in the gut and it's involved in the regulation of peristalsis. So if you give an SSRI, you have increased bowel transit time. That's perceived by the patient as being quite nauseous provoking. People often get loose bowels or diarrhoea with them, but these side effects do tend to settle down. So when you're counselling patients, you want to be saying that it's expected to get these side effects, but they will settle down within a few weeks. Um, headache is a classic for pretty much any medication. Um, you can get agitation. Akathisia is a sort of central restlessness, like feeling like you can't sit still or stand still. Um, People can get insomnia, worsening of sleep disturbance. Again, that tends to be something that settles down. Sexual dysfunction is a major topic at the moment, particularly across the social media landscape at the moment. There's lots of concern about some of the sexual side effects of SSRIs persisting beyond the withdrawal of the treatment. People on social media are talking about genital numbness or the inability to. Have orgasms. We don't know what the actual evidence is in terms of persistent side effects in this respect, but we do know that they can cause reduced orgasm while people are taking them, and it's important to counsel people for this because. It's a major cause of noncompliance and there are things you can do. So for example, I would switch to mirtazapine as a first port of call in general practise. You shouldn't start with mirtazapine, but if this is a side effect that people are concerned about, you can switch to mirtazapine. Um, there is also an antidepressant called bupropion, which doesn't have a licence in the UK, uh, but you, you might be able to prescribe that for patients with sexual side effects of SSRI's, um. Hyponatreemia is also a concern, particularly amongst older people. So when you guys are working as kind of medical SHOs, you will see older people that have been started on SSRI who come in hyponatremic perhaps having falls, and you would withdraw the treatment at that point. There is a black box warning on SSRIs for younger people. There's a concern that Um, that there may be increased suicidality in this group upon initiating these treatments, um. It's quite a rare outcome, so it's hard to measure, but it's there nevertheless. The narrative around this is that somebody could be so depressed that they don't have the motivation, drive, energy to act on their suicidal thoughts. And when you start taking an SSRI, they might have the drive motivation to act on those preexisting thoughts. For this reason, in general practise, I would suggest that you bring somebody back for a follow-up about 1 week after initiating treatment, potentially up to 2 weeks if you have to. Um, So, um, moving on a little bit to thinking about kind of how um antidepressants work because this is definitely something that your patients will be concerned about at the moment. Um, so Looking back at the pharmacology of how these drugs seem to be working has led to a series of hypotheses. Initially in the 1990s there was this monoamine hypothesis of depression emerged, and this was based on the fact that all our known antidepressants seemed to increase serotonin or noradrenaline at the synaptic cleft, and we know that amphetamines and cocaine will elevate your mood acutely. And there's some evidence that perhaps depressed patients have a low turnover of serotonin, so they have this low serotonin metabolite found in their CSF, and these observations led to this idea that perhaps depression is caused by Low levels of serotonin and noradrenaline in the synaptic cleft and that this treatment is reversing the underlying cause. We don't think of it in these sorts of terms these days, but it's important for you guys to know the historical context. Um, and we'll kind of unpack that a little bit in a bit, um. But if you sort of do a bit of Googling and and use Google to work out what people are concerned about around antidepressants, you'll discover that people want to know whether or not antidepressants work. They also seem to want to put their dogs on antidepressants, but I've even heard of dogs being put on antipsychotics recently, but anyway, that's sort of tangent. The sorts of common questions you might be asked is, you know, do they work? Definitively, yes, they do. Um, uh, psychiatry has completed a number of, um, huge pragmatic, um, uh, clinical trials looking at the actions, the action of, um, of antidepressants in the real world sort of clinic setting, um, and, um, and, and that shows that they, they, they do work. You can get about 2/3 of your patients into remission. Um, using sequential prescriptions of, of antidepressants, which is obviously nowhere near perfect, but it's it's it's fairly good. Um, how long do they take to wait? Well, potentially several weeks, um. A bit more on that later. It takes a little bit longer in the elderly and tends to respond a bit faster in younger people. How long do your patients need to keep taking them for? Well, we tend to say at least 6 months. Up to 12 months would probably be desirable. Um, and then if, if someone's had previous episodes of depression, um, we would recommend 2 years, um, at that point. Um. It's a bit arbitrary really. What I actually tend to do is talk to patients about how these medications can have a withdrawal syndrome, so it's important that that's included in your counselling when you first put somebody on antidepressants, that when they come off the antidepressants they might get a worsening of their mood symptoms, they might get increased anxiety, the insomnia might get worse for a little bit. And um And it would be best to avoid that at key points in their lives. So for example, I'm an eating disorders consultant and I see lots of young people who are going off to university. I would tend to say to people, look, if you're on antidepressants, maybe consider withdrawing them during one of your summer holidays rather than during the kind of stressful time at university. That sort of thing, like wait until everything else is aligned in your life before making those sorts of changes. But they do have a role in in in relapse prevention. There is a risk of further episodes of depression upon withdrawal of antidepressants. Um, that's the message to to to to convey to our patients. So how do they work? Let's just uh kind of go back to this idea of the monoamine hypothesis. um the main um kind of observation that goes against the monoamine hypothesis of depression, um, is the length of time it takes these treatments to work, so. I've made this observation that amphetamines and cocaine will elevate mood. I mean if I was to take an MDMA tablet tonight and go out raving, I would definitely experience increased mood pretty quickly. Why is it that antidepressants take a few weeks to have some effect on mood? Well, the answer is that it's it's not good enough to just flood your neurons with serotonin and noradrenaline. Um, there's something else that happens, um, down the line, um, that we're interested in. And I guess the question really is sort of how, what else do we know about depression since these kind of the, the, the 1990s monoamian hypothesis. Well, we now know a lot more about stress. Um, so we know that um that stress causes increased serum cortisol, um, and that that is neurotoxic, um, especially in the hippocampus. So we know that. If you, if you have if you have a stroke in the midst of a midlife midlife crisis, a major life crisis like a divorce or moving house or some significant life event has happened, and then you have a stroke, you'll have a much larger penumbra. Like that area of affected brain tissue will be much larger than if you have a stroke at some other time in your life, which shows that you know, stress, stress is affecting your brain's ability to um uh uh look after itself, I suppose, um. So let's just unpack this a little bit depressed people have got decreased levels of other neuroprotective chemicals such as BDNF. So BDNF is brain derived neurotrophic factor. You guys will know from your cell biology that in any tissue cells are constantly telling each other to stay alive. There's sort of intercellular signalling molecules that can tell each other not to go into apoptosis. In the brain, BDNF is one of these key kind of intercellular signalling molecules, and we know that people with depression have got low BDNF levels. And I think that there's a really interesting link here. Between hopelessness and neuroplasticity, so the lowest levels of BDNF that have ever been found have been in postmortem suicide cases, and it kind of makes sense to me that if you have impaired neuroplasticity, the kind of psychological corollary of that would be. Uh, um, hopelessness, because if you don't have the ability to form new pathways, then you don't have the ability to change and you need to have the ability to change in order to have hope, um. So I'm gonna bring all that together now, um just just quickly um to revise the HPA axis, so you guys have done endocrinology, I think, so you'll know that the hypothalamus produces CRH which then causes the anterior pituitary to produce a CTH which then travels to the uh adrenal cortex which produces cortisol, but then cortisol travels back to the brain. And then binds to glucocorticoid receptors centrally to switch off ACTH production normally. It's important that we do that, um, because we need to calm down after a stressful incident, we need to be able to regulate, etc. etc. But we know that people who have got depression have got raised cortisol levels. We know that the adrenals and pituitary are physically larger in depressed people. Um, and we know that there's reduced negative feedback, um, amongst depressed people too, so you can test this because you can give people, um, exogenous steroids and then you can measure their ACTH level. So normally, if you give exogenous steroids, you'd experience a shutting off of the ACTH because there's impaired negative feedback. But depressed people don't switch off their cortisol as readily as non-depressed people, and in fact it's not just depressed people, it's also anybody with a history of childhood adversity, whether or not they're currently depressed. Um, and this is, um, this is now termed kind of the glucoglu glucocorticoid resistance. Um, so your central system is resistant to, um, to cortisol. And this, this, again, this, this kind of makes intuitive sense. So imagine you're a young, you're a young child, you're growing up in an adverse environment, perhaps, um. Instead of receiving love and kindness when you seek help from your caregivers, you, you, you might run the risk of of a kind of aversive experience like you might get shouted at or you might even get abused. You know, it might be advantageous to be in a state of high alert. You know, if it's helpful to run out of your bedroom quickly because your two parents that are in the midst of a domestic violence relationship could burst in at any moment, then perhaps being in this state of increased cortisol would be advantageous. But then in later life that becomes maladaptive. We need to be able to switch off our cortisol production. Because because cortisol itself is so dangerous for our brain. And it's unnecessary. Um, so all of these, all of these, these kind of findings are now pointing towards a more um a neuroplasticity hypothesis of depression. We know that antidepressants cause a slow increase in BDNF production in the brain, and they do that via G protein coupled receptors. And we also know that antidepressants can increase glucocorticoid receptor expression centrally as well, and they do this. By affecting gene expression. So, um, serotonin binds to G-protein coupled receptors that then cause a bunch of intracellular signalling cascades that then affect gene expression. Um, And antidepressants may be directly increasing plasticity in hippocampal neurons via these mechanisms, and it also explains that that delay between initiating an antidepressant and experiencing improvement in depressive symptoms because you're waiting for new proteins to be synthesised. You might even be waiting for new. Dendrites to form and new synapses to form, so these are, you know, complex structures that your, your brain needs to kind of grow in order to get any benefit from these antidepressants. So I guess the take home message here is that antidepressants help recovery from depression by protecting the brain from further stress. They help to ameliorate that um glucocorticoid resistance that I've talked about um. And they and they allow different neural pathways to be formed. Now, I just at this moment I I just want us to just think for a second about what this means in terms of um in terms of our communication with our patients, so um. If you went to go and see a GP or a psychiatrist in the late 1990s, you would have been told that you have uh with depression, um, you'd have been told that you've got a brain disease that's caused by an imbalance of certain chemicals in your brain and that this tablet that the doctor's going to prescribe for you is going to reverse that and then you're going to feel better. What we're now saying. Is that we don't know what causes what causes depression. But we do have this medication that will improve um your brain's ability to form new pathways, um which can make change easier to bring about, um, but what would you like to change? So I suppose my point is that the that the responsibility for the illness has shifted slightly from this very paternalistic um view where um where where the doctor is responsible for the. Illness and the treatment to a sort of shared place where you can say well I have this medication that might help um but um you know we need to work together to to kind of think about what sorts of changes you want to bring about and this this might be why they work so well in conjunction with psychotherapy. So we know that if you initiate antidepressants at the same time as psychotherapy. They work with synergism. You get a better effect than if you were to give either of those interventions on their own. Um, And I think I think that we're at the stage where you can share this narrative with patients when you're initiating them on SSRIs. You can mention neuroplasticity and talk about how they can help bring about change and how that can improve levels of hope, etc. Um, So that's um that's that's our little bit on um on antidepressants. Um there's a couple of um kind of emergency psychiatry topics that we're going to sort of tick off as we go, and one of them is serotonin syndrome. um serotonin syndrome is a potentially dangerous condition where you have uh neuromuscular abnormalities, so classically sort of stiffness, rigidity, clonus, um, tremors. altered mental states of confusion with autonomic dysfunction, classically kind of hypothermia or blood pressure disturbances, and you'll become aware of this as SHOs on the medical wards or even the surgical wards because Uh, pharmacists will notice that you're prescribing tramadol to people that are also using SSRI's, um, and they'll tell you off, because tramadols, um, also has serotonergic effect. Um, but there's a, there's a, there's a whole bunch of things that can have a serotonergic effect, and it's important to try and avoid that where possible. The treatment of serotonin syndrome is really supportive, so admission to hospital, um, uh, rarely you might need to use things like cyproheptadine, but by the time you've reached that stage, you're probably talking about an ICU admission. Um So yeah, that's the first half. Um, does anyone have any questions or thoughts on antidepressants before we move on? No, um, I'm. Aware that we started a bit late, but I'm probably up for just carrying on, does that fit with, yeah. So the next bit then is about psychosis and antipsychotics, um. Uh, so we're gonna, um, hope to gain understanding of how antipsychotics have their effects and then use this knowledge to better equip you in the use and monitoring of these treatments, so. I guess the difference for this half of the talk is that I'm not expecting you to be able to initiate antipsychotics in general practise, but you will definitely have a role in monitoring long-term antipsychotic use. So if somebody's on an antipsychotic or indeed if they have schizophrenia or severe mental illness, SMI as it's termed. Then they'll go on a special register in general practise, which means that they need to have an annual physical health checkup. So you'll see patients booked in to see you and they'll come for their annual review of their medications, so you need to know what you're going to be looking for. So I'm targeting. This half of the talk on that, on that interaction. Um, So we're gonna, we're going to sort of understand them, we are going to very briefly review our dopamine physiology, um, both in the context of schizophrenia, um, but also in terms of the pharmacology of antipsychotics. I am going to introduce the concept of atypical antipsychotics and what makes the drug atypical, but I'm not going to labour that point. I'm gonna explore issues of dose and timing and then some principles of good prescribing and monitoring requirements, etc. A bit later as well. So what what is psychosis? Well, again, this was another quick Google search and um I guess the unifying theme across these images is that there's um. Uh, disturbance in perception. Um, so people experiencing psychosis perceive the world in a way that's different to the way that most people perceive the world. We would term that hallucinations or delusions, so erroneous perceptions and supposedly incorrect beliefs. I would argue that hallucinations and delusions are probably fairly similar. And we perceive the world based on our beliefs. Um, and then there's a cluster of negative symptoms involved in schizophrenia too, so flattened affect, cognitive difficulties, poor motivation, slow social withdrawal, um, and our account of schizophrenia needs to account for both of these, uh, clusters. So we're gonna go through the 4 major pathways in in the dopaminergic system. Um, I suppose, in particular, the mesolimbic tract, um. And uh the the mesocortical tract in terms of their um their function in schizophrenia, but also the nirostriatal tract and the tuber infunddibular tract in terms of the side effect profile of antipsychotics. Um, So the current thinking around the neurobiology of psychosis still centres around the dopamine hypothesis, and this was originally based on the observation that all known antipsychotics are dopamine antagonists. So in a very similar story to the discovery of antidepressants, we Discovered that a group of chemicals work as antipsychotics and then we looked at how they work in the brain, and afterwards to try and understand this, and all known antipsychotics are dopamine D2 receptor antagonists. But unlike in depression, we do also have more compelling neuroimaging evidence to suggest that there is actually an underactivity. Um, in the mesocortical pathway relative to a relative overactivity in the mesolimbic tract, um, in, in, um, psychosis, that might not be the cause of psychosis, but it's definitely a part of the story in psychosis. Um, So let's let's take um the most interesting of these pathways first. So the mesolimbic pathway, um this is the pathway that's relatively overactive in schizophrenia. It starts in the ventral tegmental area in the midbrain, and the fibres from this area then um synapse with cells in the nucleus accumbens. So if you look at the green caudate nuclear, um, yeah, caudate nucleus in this schematic, the nucleus accumbens is towards the front of that structure. And it's my favourite part of the brain, um, the reason why it's my favourite part of the brain is because it's associated with reward, um, which is fascinating. And it's also known as the so-called pleasure centre for the brain, um, so directly activated by drugs of abuse that create the experience of pleasure, but also activated by anything that causes pleasure, so you, you eat a good meal or socialise with good friends or have sex, then you will experience dopamine being released onto your nucleus succumbens. So why do we have this part of the brain? Um, because. These structures that I've been talking about are ancient structures, so we share nucleus accumbens with reptiles. They're highly conserved in terms of evolution. So they must have some kind of role, and it's kind of fairly obvious really, isn't it, that um that you need to have some kind of neurobiological system that motivates us to perform behaviours that increase the likelihood of us passing on our genes. So whether that's kind of, you know, being motivated to seek out your next meal or being motivated to find to find a mate. But it might be more complex behaviours too, so our, our little guy at the bottom there, um, he might have discovered that if he cooks his food. He releases more carbohydrates from the starches. As a result, he gets a greater sugar hit and therefore more dopamine is released onto his nuclear succumbens so he experiences more pleasure, which means that he's more motivated in the future to build a fire before cooking instead of just eating his food and you can see how it could build up some more complex behaviours and even perhaps complex social navigations as well. But what if I told you that in addition to all these pleasurable things causing dopamine release on the nucleus succumbens, what if I also told you that extreme threat um can also cause a release of dopamine onto your nucleus succumbens? um. You know, some people might say, well, then that, then we just have an explanation for why BDSM exists, um, but you know, um, uh, perhaps the word reward is not quite, um, you know, um, capturing the full, uh, the, the, the fully what's going on here. And instead, instead of using the word reward, we now, uh, talk about salience. Um, so, um, I, I should really change this slide. I've been doing this for a few years now, but there will be some people in the audience that are colorblind. Um, on this slide, I'm showing you a, a, a, a, a, a group of green dots, and in the middle of it, there's a red dot. And for most people, uh, when they look at this slide, um. The red dot will have greater significance because it stands out, and we need an ability to philtre our sensory experiences. We don't have the cognitive reserves to kind of pay attention to everything that we perceive. Um, so we need to be able to philtre, and we philtre by applying salience to experiences. In this example, the red dot has greater salience for us, so we're drawn to it and we're more interested in it. Um, So, um. There's a growing hypothesis in psychosis known as the aberrant salience hypothesis, and this suggests that the function. Of the ascending dopaminergic signal to the nucleus accumbens, it it it is about attributing salience to our experiences, um and that psychosis may be about the misattribution of salience. um, so just think about this in terms of being at a dinner party. I mean you guys are students, so you probably still have those house parties that you go to where. There are people, sort of so many people in the house that there's like kind of people sat on the stairs and you know you can barely even get in through the front door when you get there. Well, you turn up at one of these parties, right, you go into the kitchen, you fight your way through, um, and over the other side of the room, somebody's in conversation with a friend of yours, and you hear them use your name. Now, the experience of hearing your name. Is attributed with high levels of salience for you, because you've learned that that's important for your um for you. Um, so you, your attention will be grabbed quite quickly despite the hubbub of that noisy environment. You, you, you know, you zero in on that, on that experience. Why are they talking about me all this. Now imagine, imagine that you are somebody who, as a result of your neurobiological makeup, um, you know, I'm hesitating to use the word genetic, like biological makeup. Um, you attribute salience to experiences inappropriately. Well, you might be sat in this room. And there's quite a lot of background noise, right? There's like, you know, perhaps an air conditioning unit that most of us might not have noticed until just that moment ago. But if you were somebody who misattributed salience, you know, it doesn't take much of a stretch of the imagination to um kind of imagine that you might begin to hear your name in that noise. You know, you're, you're misattributing salience to that air conditioning unit and you might hear your name. Well, you'll have learned in psychiatry already that third person hallucinations are a hallmark of psychosis. Well, you know, hearing, hearing your name, somebody else saying your name is third person, isn't it? So I don't know, maybe that, maybe that sort of explains that a little bit. Um. But, but now, imagine, you know, not only have you got that biological um predisposition towards misattributing salience, but also your past has been filled with a lot of aversive experiences rather than perhaps the kind of loving kindness that we hope to raise our children, um, in, um, then you might, you know. You might begin to understand how somebody would not only experience something as being particularly relevant to them, but also perhaps being a malevolent experience rather than a benevolent experience. So, we know that blocking the mesolimbic pathway reduces the positive symptoms of psychosis, um um. I'll just flick to the next slide um because I can prove that that's the case for you. um so this um. And this Slide shows the relationship between. Um, D2 receptor. Um, binding and the known, um, therapeutic dose of antipsychotics um in the clinic, um, and you'll see that the, the relationship is, is completely linear, so the more that a that a substance binds to the D2 receptor, um, the lower the dose you need therapeutically. Um, and that this really kind of proves that the D2 receptor, um, is, is what's necessary for the treatment. Um, But just think for a second about what I've told you about this system, um, you know, and, and just reflect for a second about whether or not you would want a psychiatrist to block your D2 receptors in your nuclear succumbens. Um, I certainly wouldn't. And it might be that that is contributing to the kind of dysphoric effects of being on antipsychotics, and we know that people that use drugs of abuse and also have schizophrenia can end up using more cocaine or more alcohol after a prescriber has started them on antipsychotics almost to kind of overcome the antipsychotic antagonism effect. Um, So that's the mesolimbic pathway. The mesocortical pathway also arises from the ventral segmental area and the fibres from this pathway spread out throughout the neo neocortex and it's thought that the function of this pathway is um to um promote executive function, and potentially cognitive control of emotions as well. Um and uh a relative deficiency in this pathway is thought to underpin some of the negative symptoms of schizophrenia. But of course there's a big problem if we're, if we're giving people anti um uh a a a a dopamine antagonist, then you're not just going to affect the mesolimbic pathway which is your target, but you're also going to affect uh the uh the the mesocortical pathway and contribute to that sort of neurolaptic dysphoria. Um, The nigrastriatal pathway, you'll have come across this in neurology already, fibres from the substantia nigra innervate the striatum and dopamine released in this pathway favours movement by by by promoting activity in the direct pathway versus the indirect birth pathway. So I'm not going to do that to death, but. You'll remember from Parkinson's that you have a direct pathway and an indirect pathway, and the direct pathway favours movement, and you need dopamine in order to to activate your your direct pathway, and then if you don't have enough dopamine, either because of neurodegeneration in Parkinson's disease, or in this case, because somebody has prescribed you an antipsychotic. Then you will struggle to initiate movement, you might have tremor, you might have rigidity in your muscles. Um, Essentially, if you can examine, if you can examine someone for signs of Parkinson's, then that's what you need to do if you're asked to assess um the um the potential motor side effects of antipsychotics. So if you give a dopamine D2 antagonist then you're obviously causing Parkinson's essentially. But the motor symptom system is complicated um. And um and it can show up in other ways, so if you initiate an antipsychotic, some people will get acute dystonic reactions, um. So in that top picture there you've got somebody who's kind of having this horrible dystonic reaction in their spinal muscles. You can also get the eye muscles are often affected as well, so you can have people whose eyes suddenly roll up into the top of their head and won't come down, which can obviously be pretty distressing for people. The, the treatment of that is, is procyclidine, which is an anticholinergic, I'm not going to get into why an anticholinergic is the, is, is the treatment for it, um. You can also get akathisia, I've spoken about akathisia already, that's the sort of central restlessness, um, classically, somebody might be stood in the corner of a psych ward jogging on the spot or unable to sort of sit or stand still. It tends to settle down, but it can be pretty distressing and you do need to be thinking about potential drug effects, because of course they might have that symptom as part of their mental illness as well. Um, tardive dyskinesia is, is bad news, and it's it's something we see less of these days, but it's still worth being aware of. Tardive dyskinesia is. Classically choreiform movements are often rolling in nature, so people might smack, smack their lips or stick their tongue out, or have like repeated kind of rolling movements of their face, but it can affect other parts of the body too. Um, it tends to be irreversible, so even if you stop the antipsychotic once it's emerged, they still persist with that symptom, um. It's possibly linked to prescribing too high a dose earlier on in people's lives, so we don't tend to see as much of it these days because psychiatrists were a bit heavier handed in the past. Um, The tuberoinfundibular pathway is our 4th pathway and that links the hypothalamus to the pituitary, um, and dopamine in this pathway inhibits prolactin release. Um, so if you give an anti, an antipsychotic, so a dopamine antagonist, um, then that causes increased prolactin production, um, so symptoms of hyperprolactinemia. Um, can include. Yeah, what sort of, what sort of things might you expect to find? Gynecomastia Gynecomastia, yeah. Why might that might, why that, why might that be a problem longer term? Go on, can ask you. Yeah, yeah, absolutely, very valid, yeah, um. There's also a breast cancer risk, um, so this is quite important because I have seen people who have been on antipsychotics for decades and nobody's ever checked their prolactin, and then you check it and it's like up in the thousands and you speak to the patient like, have you, have you had a period at all? No, not had a period for decades. So amenorrhea is another symptom, or or irregular periods, low libido, um, and, and lactarrhea as well are all symptoms of hyperprolactinemia, but it's that risk of breast cancer or gynaecological cancers that is the reason why we're so keen to screen for this. Um. So summary so far, so I've I've spoken about the mesolimbic tract which is um uh dopamine signalling in this pathway is thought to um be involved in the attribution of salience and too much dopamine in that pathway may cause a misattribution of salience, and that's our therapeutic target. The mesocortical tract is involved in executive function and an underactivity in that tract might be associated with the negative symptoms of schizophrenia. The microstriatal tract favours movement through the direct pathway and blocking that can cause Parkinsonism. And blocking the dopamine and the tubero and fundibular tract can cause hyperprolactinemia with all the long term. sequelae of that. So what should be becoming clear to you is that psychiatry is a pretty blunt instrument. We bathe the entire brain in our treatments in order to target just one little bit of it. Um, so we're really kind of quite blunt. Um, we've got quite a narrow therapeutic window in terms of antipsychotics, so, um, you typically don't begin to see any improvements in. Positive symptoms of schizophrenia, until you've reached a dopamine D2 receptor occupancy of about 65 to 70%, and then and then and then when you get to 80, 85% occupancy, you start to see prolactin production and Parkinsonism, so we've got quite a narrow window. Um, but I'm gonna argue that psychiatry is maybe more here, um, because we do have, um, various strategies for increasing that window slightly, and that's. These strategies are all kind of strategies that drug companies have come up with to produce atypical antipsychotics. One of those methods is just simply to bind to the D2 receptor less tight. Um, so haloperidol is a traditional antipsychotic, and that's still bound to the D2 receptor 24 hours later, whereas quetiapine, a more modern antipsychotic, will be off the receptors within 2 to 4 hours. Um. Another strategy would be to act as a partial agonist, so, um, so a partial agonist um competes with your endogenous dopamine to get to the receptor, so it will act as a an antagonist in the presence of endogenous dopamine, but it has some downstream effect, it has an effect on the receptor that's less than dopamine itself, but does have that downstream effect anyway. Um, and aripiprazole is an example of an antipsychotic that works as a partial agonist at the D2 receptor. Um, and it's often our first choice of antidepressant, um, in first episode psychosis, um. Another way is that is that they do more than just D2 blockade, and they, they actually do a lot more than D2 blockade. So if you look at the haloperidol receptor binding profile here, you'll see that most of what what haloperidol does is D2 antagonism, but if you look at some of these more modern treatments like clozapine, risperidone, olanzapine, they're doing a lot more and, and, and. kind of complicated and I'm not going to go into the details of it, but some of the downstream effects of some of these additional receptors can be harnessed as a strategy to increase that therapeutic window. And an example is the serotonin 2A receptor. So the serotonin 2A receptor. is involved in regulating the amount of dopamine released in the nirostriatal pathway, and to cut to the chase, um, you can get more D2 blockade in your mesolimbic tract for a given amount of blockade in your nirostriatal tract if you've also got serotonin 2A binding, but like I say, you don't need to get into the details of that. Um, but there's various other mechanisms that are at play as well. But One of the problems with this is that these are dirty drugs. They, they bind to a lot of other receptors other than D2 receptors. And some some of that some of that's unwanted, and in particular, um, metabolic side effects can be quite prominent in some of these medications. So 5HT2C and H1 receptor blockade is known to increase appetite and weight gain. One of the biggest culprits for this is olanzapine, which is an antipsychotic that is pretty well tolerated, so patients. prefer olanzapine in terms of the subjective effects of it, and it's used a lot in psychiatry for that reason, um, but it can cause a huge amount of weight gain, so on average people will gain 14 kilogrammes in the 1st 12 months, so that's, you know, that's pretty significant. Like again, if you know a doctor was to say I'm putting you on this drug and it's going to cause you to gain 14 kilogrammes, I'd I'd probably tell them to get lost. But um there also seems to be an independent effect on glucose handling, so we, um, uh causing our patients to become diabetic diabetic, and that's um, um, over and above the effect on weight gain, um, excuse the pun, but it's a big problem, um. So these days can kind of share different side effect profiles with our patients a little bit more, so some antipsychotics have less of a propensity towards weight gain than others, and we should probably do a better job of counselling our patients about this and sharing the problem with them. They may lack capacity to make the decision about. Whether or not to be on an antipsychotic in the first place, but they may have the capacity to choose which one. And as if all of that wasn't enough, they can also cause prolonged QT, so you'll do an ECG um for your checkups, um, they can lower the seizure threshold, they can cause um postural hypotension, um, and um they can also cause erectile dysfunction, which is a, you know, a significant reason for noncompliance, so. One of my favourite things as a, as a very junior psychiatry SHO was to go through all of the inpatient wards and um talk to everybody on antipsychotics about um erectile dysfunction, cos you can just treat it with sildenafil or Viagra, and they think that you're the best doctor in the world and will become compliant with their antipsychotic, um, so, you know, have these conversations with people. Uh, so the, the other kind of emergency topic I was going to pick off was the neuroleptic malignant syndrome or NMS. Uh, this causes tremor, muscle cramps, fever, autonomic instability, delirium, um, so it can look very similar to serotonin syndrome, um. The key distinguishing feature is the onset, so NMS is slow onset, whereas serotonin syndrome is rapid onset. It seems to be idiosyncratic, so we can't predict who's going to get it and who isn't. There seems to be some increased risk if you're treating dementia with Lewy body. We don't know why that is. Um, in terms of your management of NMS or suspected NMS, the key investigation is CK. CK is extremely specific for NMS, so. And no, I think it's actually sensitive, so if you have an increased um uh CK, that um that's very sensitive, um. If you don't have a raised CK, you don't have NMS, um. So, um, that's important, um, because a lot of people are taken off their antipsychotics by medics, um, saying, oh they've got, they've got NMS, but they, they haven't unless they've got to raise CK to do the CK. It needs to be like up in the thousands, um. And you treat that with dopamine agonists like bro bromocriptine, but again, you wouldn't be doing that unless you're in sort of ITU at that stage. Um and and the the the mechanism of harm is the raised CK causing rhabdomyolysis and renal failure. So clozapine requires a special mention. There's evidence for use of clozapine in treatment resistant schizophrenia, so this should be offered when two or more antipsychotics have been tried unsuccessfully. Um. It was originally taken off the market because there were some deaths associated with sepsis and a granulocytosis. Because it causes a granulocytosis and thanks to a small group of psychiatrists in mainland Europe who championed clozapine, it was brought back to market, but we are required to do daily monitoring of of full blood count during the initiation of clozapine. So for a little while it was only ever given as an inpatient. These days we do manage to initiate it in the community, but it does require daily contact. You actually can't, you have to actually apply to the drug company for a kind of permission to give the drug, and you have to provide them with the full blood count results in order to get that permission. So it's taken quite seriously. Um, it can also cause hypersalivation and constipation, and it can also cause um. Myocarditis, which initially presents as a tachycardia, so the nurses on the wards will get really nervous about patients having a tachycardia. Um, But yeah, so that's worth and and the the constipation's quite relevant as well, so people have died from um uh bowel obstruction secondary to constipation, um whilst inpatients on psychiatry wards, so you know again something that you know might need to bear in mind if you find yourself doing an SHO job in psychiatry. I'm not gonna. Do this bit, but um. I guess one question that you might get asked at some point is whether or not um second generation medications are are better than 1st generation antipsychotics. Um, There's been a couple of major clinical trials. Cutlass, I think, was in the US and Katie in Europe, or it might be the other way around. Um, Looking at this and um. Essentially, the answer is there's no one antipsychotic that is better than another, um, apart from clozapine, um. And uh, I guess there is a caveat to that in that um. Because tardive dyskinesia is quite a rare outcome, these trials have not been sufficiently powered to detect the difference between atypical and typical antipsychotics in terms of tardive dyskinesia. Um, but because it's rare, it's probably not relevant to kind of, you know. I would, I would, um, Uh, decision making, um. But yeah, essentially, um. The bottom line here is that if somebody has got psychosis and they need a treatment for their psychosis, they've got a choice between almost certainly gaining loads of weight or possibly having a really dangerous persistent movement disorder. And different people with different priorities may go either way on that, on that decision, so if you're a young. Um, a, a, a young person who, you know, perhaps, you know, you work in a, say you're a model or something and you don't want to gain loads of weight, um, you might, you might be, you might be, Go, go, go one way, you know, so we need to be sharing that um that decision with our patients, um, probably more than we do. Um, So, a few words on the timing of treatment. Um, so this, um, piece of work shows that, um. If you, um, if your duration of untreated psychosis, so the period of time between your symptoms starting and you receiving your first antipsychotic, um, if that's prolonged, then your, uh your change in the PAS, which is an outcome measure used to assess psychotic symptoms, um, is, is significantly reduced. You'll notice that the Y axis is flipped on that chart. Um, and there's been more work done, um, looking at the, the early few weeks, because you'll notice also that the X axis is quite, um, is quite zoomed out, um. But um We basically know that psychosis is an emergency and that we need to get our treatments to people that are that are psychotic sooner rather than later. Um, and, um, and embarrassingly, um, GPs are better at this than psychiatrists, so if you present to your GP with psychotic symptoms, you will get an antipsychotic faster than if you present to your existing psychiatrist with new psychotic symptoms. Um, Uh, true or false, antipsychotics take 2 to 3 weeks to have an effect. And in the 70s that was certainly true, um, well, at least we thought it was. Um, and, and, and the reason for this is that objective measures such as the PAs, um, um, assessing positive symptoms are quite resistant to change. So just to kind of make that real world for you, um, if you talk to somebody and assess them. About their delusions and hallucinations, they will still report delusions within a few days of treatment, but they might be less likely to act on them. So somebody might say, my next door neighbour is involved with the Russians and there's a huge conspiracy and they're out to kill me. They might still hold that belief a few days later, but they might be less likely to go around with an axe and um take matters into their own hands, um, and this is, this is important when risk assessing because, um, you know, you might be asked to assess um the risks of letting somebody out of a seclusion suite on an inpatient ward, for example, if you know that they've had antipsychotics for the first time for a few days, then you might be um. less likely to give credence to any kind of psychopathology that they're reporting when you assess them. Uh, so in terms of discontinuation, so people might come to you and say, I'm over it now, Doctor, I want to draw a line in the sand and forget this whole thing. Well, wrong, um, there's kind of irrefutable evidence that discontinuation is associated with relapse. Um, it's about twice the risk, so for every month, um, after recovering from a psychotic, um. Uh, episode, you, you, you have a 10% chance of relapse, um, but if you're taking antipsychotic, it's a 5% chance of, of relapse, so it's, um, a significant reduction, um. And this might be due to super sensitivity, so it might be that if you block dopamine D2 receptors, one of the things that the post-synaptic cell does is up regulates its expression of D2 receptors, and then if you suddenly withdraw the antipsychotic, then you have super sensitivity, you've got loads of D2 receptors there that all get activated when there's endogenous dopamine production, um, so they can become kind of overwhelmingly psychotic straight away. Um, but, um, but, but, but, but the jury's out on that. Um, I guess the question is, are we, are we causing people to be addicted to to antipsychotics rather than sort of treating some of the kind of underlying condition. So just to bring some of these things together then into some prescribing principles, I'd say you can act fast, it's an emergency, needs treatment quickly, uh go slow in terms of escalating the dose and titrate the side effects, um listen to our patient and share the side effect profile with them and um and and and and and involve them in the decision making. Offer clozapine quickly if they've not responded to two antipsychotics and encourage compliance long term as well. And what we've done today is we've reviewed our dopamine neurophysiology. We've used this to understand psychosis as a problem of misattributed salience. You now know the difference between 1 and 2nd generation drugs, and essentially there isn't a difference, at least in terms of efficacy. And then we've reviewed the different side effects according to the um our knowledge of dopamine physiology. Um, and we've, we've said that we need to treat early and continue treatment, so, uh, anyone got any questions about antipsychotics before we end? Oh good. That's, that's it. So just a reminder then that we've not covered the mood stabilisers and in particular lithium and the monitoring requirements and side effect profile of lithium is a is a major topic that you do need to make sure you've covered at some point. Thanks a lot.