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The Neurobiology of ADHD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... The Neurobiology of ADHD Hi, and welcome back to Pay Attention: ADHD Through the Lifespan. I'm Dr. Rostain, Professor of Psychiatry and Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. And this is week !ve, where we'll be talking about the neurochemistry of ADHD. Let's begin by looking at the neurotransmitter systems of the brain. In general, there are two categories of neurotransmitters, those that are derived from monoamine, and that includes serotonin, norepinephrine, dopamine, acetylcholine, and histamine. And then there are those neurotransmitters that come from amino acids, glutamate, GABA or GABA amino butyric acid, aspartate, and glycine. Now, how do these di"erent neurotransmitters work in the brain? What are their roles? Well, !rst of all, the brain has over 100 billion neurons and many transmitter systems and subsystems. The glutamate system has over 20 billion neurons, and the GABA system has over eight billion neurons. The norepinephrine and serotonin and dopamine neurons are actually much... There are many fewer of those. There are only about 30 to 50 thousand norepinephrine neurons, and about a quarter of a million serotonin and dopamine neurons. So it turns out that the billion cell systems, the glutamate and GABA cells, they're the ones doing the work of the brain. And the thousand cell systems are really !ne-tuning these billion cell systems. So, when we think about serotonin, when we think about the catacholamines, norepinephrine, and dopamine, and when we think about histamine we have to remember that these systems are actually working on the glutamate and GABA cells, they're the !ne-tuning, if you will, of the entire system. Now, looking at the chemical structure of the monoamines that we'll be talking about, especially norepinephrine and dopamine, you'll notice that these two structures in particular look a lot alike. And there's a reason for that. It's because they are actually very closely related in the chemical pathways. So, looking at the catacholamines synthesis process. Let's begin by turning to tyrosine, which is probably the most common source of neurotransmitters in the body. If 1 of 9 6/26/24, 9:38 PM The Neurobiology of ADHD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... tyrosine is not available the body will make these neurotransmitters from phenylalanine as well. But tyrosine is the most common precursor to our neurotransmitters that we're discussing. Through a process of oxidation and decarboxylation, you end up with dopamine. If you notice, there's been a few changes in the chemical moieties, and from dopamine, when you remove hydroxylase you turn that molecule into norepinephrine. So, these are the ways in which our dopamine and norepinephrine transmitters are made. What do these transmitters really do in the brain? Well, there's an overlap of these functions. It's hard to separate them out. But, in general, norepinephrine is involved with alertness. Dopamine is involved with attention and pleasure and reward and motivation. And serotonin may modulate anxiety and mood and obsessions and a lot of our appetites. Notice that all of them are involved in mood regulation as well. When we look at catacholamines and brain activity it's important to keep in mind that these di"erent pathways originate deep in the brain, and these transmitters are neural tracks that go from deep in the brain to all of the di"erent parts of the brain that we've been talking about that are important in ADHD. For example, the dorsal lateral prefrontal cortex, the visual cortex. These are innervated by neurons that originate, the tracks that originate deeper in the brain, from the ventral tegmental area and the substantia nigra come dopamine pathways, which I will be describing a little bit later, from the locus coeruleus come pathways that are rich in norepinephrine. And from the nucleus basalis come acetylcholine !bers, again, distributed widely across the brain. Now, what are the neuro chemical de!cits we see in ADHD? Well, for one thing, we see dopamine dysregulation. For another, we see norepinephrine dysregulation. The evidence for this comes from drug studies. For example, we know that stimulants increase dopamine and methylphenidate and amphetamines change the rate at which neurotransmitters are either released or taken up. Another medication, atomoxetine, works on the norepinephrine system. So, from drug studies, we know that dopamine and norepinephrine regulation can be a"ected in ADHD and can be helped by medications that address that dysregulation. As we talked about early, molecular genetics is also important in getting us to think about dopamine and norepinephrine regulators because the genes that have been most likely linked to ADHD are involved in these two transmitters. And !nally, when we look at neurotransmitters in the brain regions associated with 2 of 9 6/26/24, 9:38 PM The Neurobiology of ADHD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... ADHD, these are brain regions very rich in dopamine and very rich in norepinephrine. You may recognize this slide from a few weeks back, and I'm returning to it only to point out, once again, that the dopamine system and the norepinephrine cells that originate deep in the brain have important functional linkages to the areas of the brain that we've been talking about, the interior cingulate and the prefrontal cortex, as well as the posterior parietal cortex. And that these transmitters then regulate the activity of all of the other cells in the brain. Dopamine is a key transmitter, we've already said. What are some of its functions? Well, dopamine helps control movement, it modulates reward systems, it keeps us motivated, it allows us to pay attention, it's involved in the experience of pain or pleasure, and dopamine is also involved in emotions. And, as I said before, dopamine modulates neuro circuits in the cortex and the basal ganglia. And these circuits that are listed here have been introduced earlier in our neuroanatomy lectures, but these are dopamine-rich circuits, the dorsal lateral prefrontal cortex, the orbital frontal cortex, the anterior singular cortex, the insular cortex, the limbic system, and the nucleus accumbens. All of these are very much a"ected by dopamine activity. When we look at what dopamine does in general to these key pathways in ADHD we see that dopamine enhances signal conduction and improves attention. It allows us to focus, it allows us to maintain on-task behavior, and it allows us to think and stay thinking about a particular task that we are interested in solving. So, once again, the dopaminergic system is involved in attention. Let's turn now to the actual way in which dopamine is functioning at the level of the synapse. This is a diagram of a neuronal synapse. There's the presynaptic terminal and the postsynaptic terminal. And what you can see in the presynaptic terminal is that tyrosine is converted to L-DOPA, and then from L-DOPA dopamine is created. What happens to the dopamine? The dopamine is stored in a vesical. It stays there until a signal comes along. When a signal comes along and there's a need for the transmitter to be released the vesical moves to the end of the membrane and releases the dopamine into the synaptic space where it crosses the space and it sends the signal across through the receptor to the next neuron. This is the basic principle of neurotransmission. Dopamine is synthesized, dopamine is stored, dopamine is released, and then once it's released it activates the postsynaptic receptor so that the signal can be sent down further down the next neuron. 3 of 9 6/26/24, 9:38 PM The Neurobiology of ADHD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... Now, you will notice that there are MAO inhibitors located in the presynaptic terminal. These break down the dopamine when it needs to be broken down and made again. There are also other enzymes called COMT inhib... And the COMT also is involved... COMT, which stands for Catechol-O-methyltransferase. Let me start again. Can I start this whole segment of transporter one more time? All right, I'm gonna start this slide over again. You tell me when. Let's review brie#y dopamine neurotransmission. This is a diagram illustrating a dopamine neuron and its looking at a presynaptic terminal and another neuron where the receptor is visualized in this diagram. A signal coming down this neuron triggers the release of dopamine into the synaptic pathway. Wait a minute. I skipped the whole... I don't even know what I'm doing today. Hold on. One more time. Apologize. I skipped the whole how it's made, right? Okay. And one, two, three. Let's look brie#y at how dopamine neurotransmission works. As I outlined before, tyrosine gets converted to L-DOPA, and then also then gets transformed into dopamine, which is stored in presynaptic vesicles. This is the presynaptic terminal of a neuron. Now, that dopamine sometimes gets broken down by MAO inhibitors, and then it gets recycled and more dopamine is made. So there's a continuous recycling of the dopamine supply itself. When a signal comes down the neuron dopamine is released into the synapse, crosses the synapse and begins to send a signal across the receptor. So the receptor is there to receive the dopamine. Once the dopamine interacts with the receptor the signal is sent down the nerve path that the other neuron. At the receptor side we have enzymes called catecholamine omethyltransferase, catechol omethyltransferase enzymes that break down the dopamine in the receptor side. Once dopamine is released it is taken back up into the neuron and repackaged. So there is a recycling going on in the neuron that allows dopamine that's made to be released and taken back up. And it is at this dopamine transporter site that many of our medications work. 4 of 9 6/26/24, 9:38 PM The Neurobiology of ADHD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... Dopamine clearance is regulated by these three major systems. First there's the dopamine transporter protein, which is responsible for the reuptake of dopamine from the synapse, there's the monoamine oxidase system, which breaks down the dopamine, and there's the catechol omethyltransferase, or COMT, system that breaks down dopamine as well. Turns out, of course, as I mentioned before, the genetic studies of ADHD have looked at genes that code for these di"erent systems, for the transporters, for the monoamine oxidase and for the COMT transferase. Now, looking at how medications work, it turns out that PET imaging studies have identi!ed that methylphenidate changes the amount of dopamine in certain extracellular spaces, in particular, in the basil ganglia. And what it looks like happens with stimulants like methylphenidate is that there's an ampli!cation of the dopamine signal. It turns out, though, that the e"ects of these medications are context dependent. So, what really is happening is that dopamine enhances task-speci!c neuronal signaling and decreases the noise. So, what happens is that methylphenidate may work by improving attention through decreasing distractibility or maybe making tasks that are otherwise boring more interesting. We'll talk a lot more about how medications work later on in the course. But I think it's important to discuss this now, to point out that it's precisely the dopamine system that is modulated by most of the medications that we use to treat ADHD. Let's turn to the other major neurotransmitter, norepinephrine. Norepinephrine acts on postsynaptic Alpha 2 receptors, of which there are three subtypes, A, B, and C. Most of the Alpha 2 receptors are postsynaptic to norepinephrine cells. So, for example, the dendritic spines of the prefrontal cortex pyramidal cells have many of these receptors. The most important subtype is the A subtype. We think that this is responsible for the way the prefrontal cortex can be modulated by norepinephrine. So, norepinephrine signals are important in enhancing the network connections of the prefrontal cortex largely through Alpha 2A receptor stimulation. Norepinephrine, which originates in the locus coeruleus and has connections all throughout the brain, in particular in the frontal cortex, helps to dampen the noise, enhance the executive operations and increase the inhibitory functions of the frontal lobe. It allows us to look before we leap, to think before we act. So, this is where we 5 of 9 6/26/24, 9:38 PM The Neurobiology of ADHD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... think norepinephrine plays a role in ADHD. Looking again at norepinephrine neurotransmission, which resembles that of dopamine transmission. You can see that in the presynaptic terminal tyrosine is changed into dopa, and then into dopamine, and !nally into norepinephrine, which is stored in the vesicle. The norepinephrine, when the signal comes along, is released into the synapse, and from there travels across the synapse to the receptors at the postsynaptic terminal. Now, after the signals are completed there is a reuptake process that's mediated by the norepinephrine transporter. Once the norepinephrine is taken back into the cell it might be broken down by MAO, or it might just be repackaged into the vesicle to be released again with the next signal. Note also that in the post synaptic terminal there are Catechol-O-methyltransferase enzymes that can also break down the norepinephrine. So, this is an elegant system for maintaining a balanced amount of norepinephrine, and we believe that in individuals with ADHD both the norepinephrine system and the dopamine system are not regulated properly. It's not that these transmitters are absent, it's just that they're not being regulated properly. Let's try to put all this together. And I'm going to summarize what you've heard so far. First of all, there is the synthases and the metabolism of all of the neurotransmitters that I've described, and there are many modulators, by the way, in how these function. But, as we mentioned before, dopamine beta hydroxylase and Catechol- O-methyltransferase and monoamine oxidase, they're all involved in the synthases and the metabolism of these two major neurotransmitter systems, norepinephrine and dopamine. They all interface with the workhorses, glutamate, GABA, and NMDA and AMPA, which we haven't discussed, but which are also amino acid derived neurotransmitters. What happens then? Let's begin with the brain getting sensory input from the outside world. Where does that sensory input go? It goes to the posterior parietal cortex eventually, which is where we assemble all of the di"erent signals, from sights and sounds and other sensory modalities into a picture of what's going on. That's largely... The posterior parietal cortex is heavily enriched with norepinephrine transporters, the Alpha 2A type. As we discussed before, there's a very rich connection between this part of the brain 6 of 9 6/26/24, 9:38 PM The Neurobiology of ADHD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... and the prefrontal cortex, which is rich in di"erent dopamine and norepinephrine transporters and dopamine receptors. This connects back to the striatum or the movement areas of the brain, the basal ganglia. Again, dopamine transporters and D2 receptors, which again then are linked also between the cerebellum and the prefrontal cortex where D3 and D4 receptors in the cerebellum are activated through these pathways. So you can see how this begins to get into a complex circuitry, which then, all of which depend on the proper functioning of both the dopamine in blue and the locus coeruleus in red centers deeper in the brain. These centers, then, enhance the signal. In the case of norepinephrine, enhances the relevant signals of the parietal cortex. In other words, it allows the parietal cortex to do its job better. And also, norepinephrine allows the prefrontal cortex to work better, not only by enhancing relevant signal, but by also modulating and regulating dopamine. And !nally, dopamine suppresses the irrelevant signals and allows us to focus on what's important. So this is a way of diagramming all of the complicated interactions between these di"erent brain centers and the neurochemical pathways that are involved in signaling and transmitting information between all of them. Let me turn now to a summary of the neurobiology of ADHD that we've been discussing for the !rst several weeks of this course. We can start by looking at ADHD symptoms as we discussed in week one. There are combined ADHD individuals for those that are predominantly inattentive, or those that are predominantly hyperactive and impulsive. These are the symptoms. Where do the symptoms arise from? Well, the symptoms arise from di"erences in basic processes of the brain. And we've talked about executive function and motivation. Under executive function, we can talk about working memory or behavioral inhibition. And these are topics that I will be discussing next week. We also can talk about motivation and the di$culty with either postponing reward, which is called delay aversion, or by being reinforced by whatever is going on that we're engaged in. So, these basic processes themselves may explain the symptoms of ADHD. But what gives rise to these changes in the processes? Well, these are the neuromechanism below hand, which we've been talking about, the prefrontal cortex, which is involved in both executive function and motivation, the basil ganglia, and the 7 of 9 6/26/24, 9:38 PM The Neurobiology of ADHD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... cerebellum. These are the key brain structures. And what allows those brain structures to work properly are the neurotransmitters we've been discussing. In this diagram, it says noradrenaline, that's the same as norepinephrine, dopamine also. Serotonin we have not discussed, but this is also perhaps a modulator of the brain functioning we're discussing. We've been focusing mostly on norepinephrine and dopamine. And, certainly, last but not least, at the most basic level, we can talk about the genes that may be altered in individuals with ADHD. All of these are the gene variations that I discussed when we talked about the genetics of ADHD. And it's changes in these gene structures that lead to changes in the way in which the norepinephrine or dopamine system is working. So we've got now multiple levels to understand, from genes to neuromechanisms to basic processes to the symptoms themselves. One day we'll know a lot more about how all of this works, but for now this is a summary of what we've learned so far. Let's turn now to a summary of the developmental pathophysiology of ADHD that's been suggested by Dr. Steve [Forone 00:24:20] and colleagues from Harvard. In this model we want to understand how is it that people with ADHD go through life, and what leads to either better or worse outcomes. Starting with the genetic predisposition we saw that early environmental insults like maternal smoking and obstetric complications can make it more likely that the individual becomes an ADHD child. And ADHD is a frontal subcortical catecholamine dysfunction disorder. I know that sounds like a mouthful, but that's really what we're talking about. We're talking about brain circuits that are not working properly in part because the neurotransmitters themselves are not being regulated properly. We can see ADHD in children, but some of them remit, some of them get better. For them, after a period of time they seem to be indistinguishable from children without ADHD. So this would be the group that we'd say remits. But there are others for whom ADHD does not go away, and in fact may get worse. And in these individuals we could talk about late environmental insults, such as substance abuse or social adversity, trouble in school. That leads to further brain dysfunction and comorbidities and chronic, chronic dysfunction. So, these individuals are at much 8 of 9 6/26/24, 9:38 PM The Neurobiology of ADHD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... higher risk for needing intervention. Finally, if the ADHD remains untreated or unresponsive to e"orts and we see then secondary e"ects like low self-esteem and school failure and social disability we then see the disorder in adults. What Dr. Forone is suggesting is that from a genetic predisposition and both early and later environmental insults individuals can be left with residual e"ects that will a"ect their entire life beyond. And so, adult ADHD then becomes the !nal outcome of childhood ADHD. And we will be talking more in detail next time about the psychology of ADHD, how it a"ects thinking and how it a"ects performance in a variety of important tasks. Look forward to seeing you next week. Take care. Print this page 9 of 9 6/26/24, 9:38 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... Stimulant and Non-stimulant Medications for ADD OK, so we're going to change up the game a little bit here. In our !rst slide set we talked about medications to help patients sleep. And now we're going to talk about medications that, oh, maybe don't necessarily help keep you awake, but certainly do keep you focused. And primarily that's a decision we have to make when we are treating ADD. ADD as a diagnosis, of course, will be further explored in your assessment, diagnosis, and management classes. I believe 69, 71-- maybe 69, 70, 71, one of those assessment courses, will talk more about history gathering, how to di"erentiate the inability to focus from other diagnoses. But now here in psychopharmacology we're going to presume that we have made a diagnosis of ADD. And now the choice is, do we use a stimulant medication or a non- stimulant medication? And as always, I do feel compelled to point out that even when medications are indicated, anyone who is medicated for ADD should also be advised to seek a therapist. If it's an adult, they need a therapist for themselves primarily to help maybe identify non-drug related ways to manage their environment, to manage their circumstances. So that they can work with their symptoms without necessarily having to rely on medications on a daily basis. And for children, especially young children, many times the family unit needs therapy. Family therapy is advised for very young kids. They can talk about things like play and play therapy and what to do when they feel frustrated or have behavior that they can direct another way. But very often parents and siblings, they don't understand it neither. They don't understand it either, and they need some help in managing the consequences of living with a child with ADD. But our focus now is medication, and that's what we're going to talk about. As a foundation to considering pharmacotherapy for ADD, it is important to have a sense of 1 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... what the problem is and what is the physiologic dysfunction, is what I'm trying to say. And we know-- and like everything else, there is certainly an environmental component. But we know that in patients that truly have ADD, there are two neurotransmitters that are dysregulated, primarily in prefrontal pathways. As your slide says, there are several postulated physiologic mechanisms. But the two targets of therapy, the two things that we know that if we regulate these neurotransmitters in certain functional areas, the symptoms of ADD will improve. And right now these are the primary treatment targets. And they are dopamine and norepinephrine. We're going to get our best symptom control when we can regulate dopamine and norepinephrine. The interesting thing about ADD is that it's not necessarily a case of too little dopamine activity or too little norepinephrine activity. It appears that there is dysregulation. In other words, there might be, in some patients, excess dopamine activity in certain prefrontal pathways, and/or excess norepinephrine activity. Or decreased activity of these neurotransmitters in necessary pathways. Or you could have an excess of one and a de!ciency of another. Or you could have a de!ciency of one, and the other one's normal. Like there's all sorts of ways that ADD can manifest. So we characterize it as dysregulation. The concentration of neurotransmitter at the relevant neural pathways is dysregulated. And the purpose of drug therapy is to regulate it. And we do see this in many aspects of medicine. It's kind of an interesting phenomenon. If you don't have a problem, if your physiology is normal and you take a medication that a"ects that physiology, it's not going to make any real di"erence. But if the physiology is abnormal and you take medication, it will make a di"erence. The best example I can give you would be with some of the hypertensive medications. So we use things like ACE inhibitors, angiotensin receptor blockers, even beta blockers, to manage hypertension. And if your blood pressure is high, then those medications will bring it down. But we also use those medications for other things. We use angiotensin converting enzyme inhibitors and angiotensin receptor blockers to treat patients with congestive heart failure. We use beta blockers for lots of things. We use them for coronary artery 2 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... disease, we use them for migraine prophylaxis, we use them for anger management. And any of these medicines, if you use them for other things in a patient who does not have a blood pressure problem, the drug doesn't really a"ect their blood pressure. So it's sort of the same thing here. If you have dysregulation of one or both of these neurotransmitters, and you take an ADD medication, it will normalize or help normalize that neurotransmitter, and you see symptom improvement. But if you take the medication and you don't have a neurotransmitter problem, it won't make any meaningful di"erence in that functional area of the brain, and you won't see any real di"erence in the way that people function. And so this is the working physiologic theory of ADD, that there are neurochemical dysregulation, including dopamine and norepinephrine. And we make-- we, science. I mean, not me personally, but the scienti!c community has made this deduction based on the things that are listed here. Response to drug therapy is a big one. And this is huge. In ADD, stimulant therapy, especially, is one of the most e#cacious treatments in the world of psychiatry. If the patient truly has ADD, and you give them a stimulant medication, the symptoms will improve. I mean, I'm not suggesting that anything is a glass pond and it will all be perfect, but there will be clear recognizable symptom improvement with taking a stimulant. Really, one of the easiest and fastest ways, if you're genuinely not sure of your diagnosis, is to try the patient on a stimulant for a week and see if it makes any di"erence. If it's going to make a di"erence, it's going to make it right away. Now, you might still have to titrate the medication, you might still have to manage adverse e"ects. I mean, I'm not saying it's going to be perfect with one dose. But I am saying, for sure, that if the patient truly has ADD, and you put them on a stimulant, there will be clear identi!able distinct symptom improvement. So one of the reasons we know that they work is because we can see that they work. There also does tend to be a genetic predisposition to this, like so many other things. And so if the family unit has-- the parent has ADD or a sibling has ADD, the likelihood that this patient does is higher. And so we can tell by the way the family responds to drugs. And then also tracking these neurotransmitters has been done with radio label tagged 3 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... scanning. The patients are given a tag that attaches to neurotransmitters, and then the brain is scanned in people with known diagnosis. And you can see di"erences in neurotransmitter concentration, and people with the diagnosis, as compared to those that don't have ADD. Why the dysregulation happens, genetics has something to do with it. It almost always does. But there appears to be more to it than that. Because, again, we always come back to the same thing, monozygotic twins are often studied for many conditions to try to evaluate the degree of genetic predisposition. And even monozygotic twins, where they share the same DNA, you'll have one twin that has ADD and the other one that doesn't. So the incidence is higher in monozygotic twins. It de!nitely supports a genetic tendency. But there is, of course, an environmental component too. But why it happens, that will be for some other scientists to describe long after I'm retired. But what we do know right now is that we know that there is a dysregulation of dopamine and norepinephrine. And mostly we know that because when we give them medicines to correct those dysregulations, patients get better. Now, we've talked about dopamine already. Dopamine, I mean, it is responsible for a wide variety of neural processes. Remember, I think I discussed with you the very !rst week of this course that we have a handful of neurotransmitters all over the brain. And they do di"erent things in di"erent neural pathways. So an imbalance in dopamine in one area can cause one set of problems, an imbalance of dopamine somewhere else can cause another set of problems. You certainly saw that last week in week four when we were talking about psychosis. So dopamine now in ADD, the dysregulation of dopamine can lead to a di"erent type of problem because it's di"erent neural pathways. So remember that dopamine is responsible for-- it is the feel good neurotransmitter, there's no doubt about it. It maintains that reward, motivation, phenomenon which is critical in the ability to attend to a task. You have to be getting something positive out of focusing on something to continue to do it. It doesn't necessarily have to be euphoria. Like it doesn't have to be, oh my gosh, this is like the best thing ever in the whole world, but there has to be some level of positive reward. For instance, listening to this lecture, listening to me talk, there needs to be some reward in it for you for you to continue to pay attention. 4 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... You might think it's a little dry, you might think it's a little boring. But if there's a reward in it for you, you will keep paying attention, assuming that you have normal dopamine concentrations, that you're not dysregulating. For instance, everybody comes to this course with a di"erent level of history and background. So some of you may be very familiar with all of this. You know almost all of what I'm talking about, if not more. If you've worked in psych for a long time and you specialize in patients with ADD, you probably know more about this than I do. So listening to this lecture, there is no particular reward in it for you. And you'll probably !nd yourself, like, you're listening because you're afraid it's going to be a quiz or a discussion board or a test, but your mind is traveling, you're paying attention to di"erent things, maybe checking your Instagram, blah, blah, blah. Because it's hard to attend to the lecture, because there's no particular reward in it for you. On the $ip side, if you are either new to psych or maybe your experience is like something totally di"erent and you don't really know anything about this, or you have a particular interest in it and you want to work with patients with ADD. For whatever reason, it would be really bene!cial for you to learn something about it. So for you the reward in listening is there. So you are going to listen, you are going to focus, you are going to pay attention, assuming that you do not have a dysregulation of dopamine. So that's what I'm talking about when I say reward. It doesn't have to be like, oh, euphoria, and I'm on cloud nine. But there needs to be something in it for you. And people that have dopamine dysregulation, sometimes even when they really want to pay attention, they can't because they're not getting the dopamine patterns that allow them to do that. Now, of course, the other thing about dopamine that you want to keep in mind is that dopamine-- remember that nigrostriatal pathway that we talked about in week four when we were talking about psychosis. And I said that dopamine is a really important neurotransmitter in those extrapyramidal and extrapyramidal tracts. So while dysregulation in dopamine in di"erent prefrontal pathways can lead to a problem attending to task, dysregulation of dopamine in your extrapyramidal tracts can lead to dysregulation or an inability to control purposeful movement. And that's what produces, or at least in part, that's what produces the hyperactivity, the inability to sit still. 5 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... Now norepinephrine is a little bit di"erent. Norepinephrine, again, has multiple roles throughout the brain in the entire body. But when we're talking about its role in the ability to attend to task, to control impulsivity, and to sit still, norepinephrine's role is a little bit di"erent than dopamine. Whereas dopamine helps you attend-- it gives you the reward to stay focused on what's in front of you, norepinephrine helps to minimize distraction. The way it's phrased on your handout here as it says, enhances prefrontal cortex network connections, and helps dampen background noise. And by background noise we mean background stimuli. Not necessarily noise, but anything in your visual !eld or even your cognitive !eld, it helps to-- it just helps to prioritize. In proper regulation, if you have proper regulation of norepinephrine, you will certainly be aware of other things going on in your environment. But you can prioritize the thing you need to focus upon, as compared to those things that are in the background. So you can see how optimal regulation of both neurotransmitters really is necessary to be able to appropriately focus on a task, while simultaneously being aware of what else is going on in your environment. But not distracted or consumed by it, by being able to control your reaction. In other words-- well, actually, let's see what the next slide says. I think that might give an example. And if not, then, of course, I will have one for you. Let's see Dysregulation, OK. So, like I said, dopamine is the thing that helps you focus. Now, I know soon I'm going to have to stop using this video, this up picture because nobody's going to know what I'm talking about because it's been so long ago. But maybe you could ask your parents or grandparents, depending on how old you are. Once upon a time before we had cable and before we had satellite TV, we got our TV pictures by way of antenna. There were major networks, ABC, NBC, and CBS, and that's where all the TV shows came from. And you got them in your house because you had an antenna either on the roof of your house. And most people had what we used to call rabbit ears on the top of a TV. And if the rabbit ears weren't quite in the right position, you wouldn't get a very good picture. The picture would be like fuzzy and hard to see and lots of wavy lines through it. I can remember my dad standing there adjusting those damn rabbit ears over and 6 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... over again, trying to get something to tune in just right. So if you remember that, awesome. If you don't, I'm open to suggestions for a new example here. But dopamine is the rabbit ears. Dopamine is the way that your brain can get focused on a particular thing. You can't watch the TV show if it's not tuned in well. And it's not going to be tuned in well with dysregulations in dopamine. Conversely, norepinephrine, like I said, it's the ability to weed out distraction. And so you could have perfect dopamine activity, and the TV is focused in front of you beautifully. It could even be like high def. But if you can't weed out the background distraction, if you can't prioritize what you focus on, then you're not going to be able to pay attention to that TV, no matter how perfect the picture is. It's norepinephrine that helps you weed out the distraction. And what you've got in front of you-- so in the dopamine picture, Charlie Brown is just sitting there looking at the TV. There's no window, there's no Snoopy on a swing, there's nothing else going on. There's just Charlie Brown and the TV. But if he's got dysregulated dopamine and he can't tune in that picture, he's not going to pay attention to it. On the $ip side, just imagine that the TV is in front of that classroom perfectly tuned in, beautiful picture. But if there is a norepinephrine dysregulation, Charlie Brown won't be able to focus on it because he is so easily distracted by everything else that's going on. People with norepinephrine regulation, they might be aware of something going on outside the window, but it's not important, it doesn't require their attention. Because of their regulated norepinephrine, they are able to acknowledge that it's there and deprioritize it. But someone who's got a norepinephrine dysregulation, they can't do that. That thing becomes as important in their prefrontal cortex as the TV, as the thing they're supposed to be focused on. So like I said, I know I'm going to be little old, and using this example may not be directly relevant to everybody. But if anybody has a better suggestion, please, do let me know. But that's the deal here. Some people will have abnormalities of one, some will have abnormalities of the other, many will have abnormalities of both. That abnormality may be either too much activity or not enough activity. And that's why ADD can present so many di"erent ways. There's a lot of criteria. Like, not all ADD is the same. 7 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... Again, we'll talk more about this in your diagnosis and management class. But you could have !ve di"erent people in front of you, and they all meet diagnostic criteria for ADD, and all of their symptoms are di"erent. And that's because of all the di"erent ways in which these dysregulations can cause problems. OK, but anyway, that is the foundation. Now let's take a look at some drugs. All right, so when we think about medicating ADD, psychostimulants really are the drug of choice. They are the absolute most e#cacious medication for the patient with ADD. I mentioned before, and you can see it on this slide, these will achieve an average 70% symptom reduction, which is enormous. Again, with almost everything in medicine, we don't medicate people with a disease to try to get them to be, quote, "Normal" or the same as people without disease. That's not possible. Medicating a disease is always about getting to that place where the bene!t of medication optimally outweighs the risk, because every medication has a risk. I'm sure that one of the things you learned in your !rst more general pharmacology class is that all medicine is a poison. Every medicine is a poison, whether it's Motrin or Tylenol or whatever. All drugs are poison. The only question always is, does the bene!t of the poison outweigh the risk? And thankfully, in many cases, it does. And this is no exception. So when you think about prescribing medications for people, you recognize that every medication can conceivably cause problems. It can cause unintended consequences, it can cause adverse e"ects that are visible right away, or that may not show up for many years down the line. But never forget that all drugs potentially have an adverse e"ect phenomenon, because all drugs are poisons. The only question is, does the bene!t of the medication outweigh the risk of a problem later? Or does it outweigh the annoying adverse e"ects that the patient might feel now? So don't ever expect to medicate somebody and have them become, quote, "Normal." Just expect to medicate them to the point where the bene!t of the drug optimally outweighs the risks. I mean, think about it, in diabetes, a normal hemoglobin A1C is 5.6%. But we don't medicate diabetics to 5.6%, we medicate them to an A1C of less than 7% because that's the sweet spot where the bene!t of medication optimally outweighs the risks. You start medicating more aggressively, you run the risk of hypoglycemia, which can be dangerous. 8 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... With asthma, we don't try to medicate the person to the extent that they will never ever again have bronchospasm. What we are doing is medicating them to the point where they have bronchospasm less than twice a week, that's considered a cure. Pain management, the goal of pain management is not the complete obliteration of pain, that's almost impossible. The goal of pain management is to reduce their pain by at least 50% of its baseline, and to get them to the point where they can function. So, anyways, I know I digress a little bit as I have a tendency to do, but it's the same thing here. The goal of any medication in psychiatry isn't normal, the goal is to get to that place where the bene!t of meds optimally outweighs the risks. And psychostimulants are among the most successful of all psychiatric medications, because you can typically achieve a 70% symptom reduction, which is enormous. But one of the many reasons I perseverate on this point is that managing patient expectation is enormous. You don't want the patients or the parents, in the case of a child patient, you don't want them expecting that they're going to take this pill, and that their child is suddenly going to be the most docile little well-behaved sitting there child. That's not realistic. What we're looking for is a signi!cant reduction in symptoms so that the child can get through the school day, get through at home, things like that. And a 70% symptom reduction is a really good reduction. It's considered really, really successful. And it happens because psychostimulants modulate both dopamine and norepinephrine. If the patient has excess activity of one or both of these, it tones it down. If the patients have de!ciencies of one or both of these, these drugs amp them up. They modulate the amount of dopamine and norepinephrine. And that's how they work and that's how we get such a good outcome. They modulate both the neurotransmitters that are a problem here. And another point to keep in mind is that when we are evaluating the patients and follow up, you made a diagnosis, you decide this is the drug, you put them on it, and they come back in for a follow up. What we're looking for is symptom control, not functional outcomes. And that might seem like a !ne line or like splitting hairs here, but you have to be careful. Because especially when it's the child with the problem, the parents are looking for functional outcomes. The parents bring in the child because they're getting in trouble in school, their grades are falling, they're always getting detention, the parents 9 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... are complaining, that kind of thing. And they're wanting medications to make the child do better in school and not get in trouble in school. And that's not really the goal of pharmacotherapy. You can't take a C student and put them on a med and make them an A student. Sometimes you'll take a C student and put them on medications, and they might improve to a B student because since they can focus better and sit still and pay attention, their work might improve a bit. But it's just-- I guess the point I'm trying to make, and I'm not doing it very well, is that when you see the patient in follow up your measure of success isn't, oh, is she getting A's now? Your measure of success is as you go through the symptom assessment, things like, is the patient losing things a lot? Is the patient still interrupting when talking to? Like, those kinds of things, you're looking for improvement in them. You just have to watch that functional outcomes because sometimes people will think that once they get on medications, they will function better in certain ways that are bene!cial. I'll give you a brief example. I have a patient, 42-year-old male with ADD. And when he !rst came to see me, his ADD, among other things, was making it very di#cult him for him to be e"ective at work. He was a mortgage writer, and part of his pay was volume-based. In other words, the more mortgages he underwrote, the more money he would make. And so for him, productivity was directly linked to pay. And because of his ADD, he was !nding it really hard to just pay attention, stay on track, and get stu" done. And his income was su"ering over it. So once he was properly medicated, he did start performing better at work, and his rate of pay obviously went up. So the next thing I know, his coworkers are making appointments, wanting that pill that's going to make them work better. And so therein lies the rub. The goal of the pill isn't to make you write more mortgages, the goal of the pill is to help you focus. If that helps you subsequently write more mortgages, that's great. But that's not the outcome that we are looking for. OK, so the !rst point of interest is that psychostimulants are the drug of choice. They are the best. If you think that somebody has ADD, if you make that diagnosis and you want to medicate them, the psychostimulants are the best drugs we have. You're going to get the greatest outcomes. 10 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... And there are two general categories, methylphenidates, of which the prototype is Ritalin. And amphetamine salts of which the prototype is Adderall. Nowadays there are like numerous derivations of each one. We have short acting, long acting, ultra long acting, we have patches, we have sublingual dissolve, we have oral pills. I mean, there's all kinds of ways you can give this stu", but they are all derivations of the two broad categories, methylphenidate and amphetamine salt. And they really are the same. I mean, they're like Coke and Pepsi. The subtle di"erence is that sometimes people do better with one than the other. There's not always a good explanation for it. But just like some people like Coke better than Pepsi for no obvious reason except that they just do. So if you're trying to pick one or the other, it really comes down, !rst, to what the patient's insurance will pay for or what they have access to. I have a tendency to start with amphetamine salts just, I don't know why, because that's how I was trained and that's what I do, and most of the time it works. And I just do. No real good reason for it. And I have had patients who will use and will use Adderall or an Adderall derivative, and they tell me that it is improving their symptoms. They are doing better with respect to focus and attention and impulsivity, but the adverse e"ect pro!le is troublesome. I mean, there are stimulants, they do make people sometimes stay awake, later in the day they might have a little bit of a tremor, some patients will get headaches. They are appetite suppressants which, of course, I would love but some people don't want their appetite suppressed. So there are adverse e"ects here. And when I have a patient tell me that it's helping their symptoms, but the side e"ects are a problem, then we'll switch to the other one, to the methylphenidate. And sometimes they just do better with that, for who knows why. But they just do better. But, truly, these two are more the same than di"erent. The only reason to pick one over the other, as a starting point, is which one is most readily accessible to them, with respect to insurance, and then see how they do with it. They both do the same thing. They both control symptoms, they both have all di"erent dose formulations available, they both have a very similar adverse e"ect pro!le. It's true some people, for whatever reason. Again, it's the Coke, Pepsi analogy, who knows why. Some people just do better with one or the other. 11 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... They are classed, they are schedule II controlled substance. They are right up there in the same class with opioids, with oxycodone, and stu". So there is de!nitely a potential for abuse. And there's like an urban legend that the amphetamine salts are more subject to abuse than the methylphenidate. It is an urban legend, I don't know where it came from. There is absolutely no evidence to support it. They both have a potential for abuse, and that's why patient selection really does include thinking about if you have any concerns at all about the patient abusing this drug. When they're used properly, the adverse e"ect pro!le truly is very limited. Notice emphasis on when used properly. These are not really intended to be, pop one because you have a test and you want to do better. Like, that's not the way that they should be. Because if that's what people are doing, they pop one before a test because they want to do better, maybe they didn't do so well on that test and the next time they pop two, and the next time pop three, you see where we're going. Of course, adverse e"ects are going to be worse if the patient is self-titrating their medication. But when these medications are given as prescribed, the adverse e"ect pro!le really is very limited. Appetite suppression is common. As I mentioned, for many adult patients this is not a huge concern. But for children, it can be a concern. Remember, kids are little-- they're just little metabolic machines. They require more calories per kilogram of body weight than adults. Growth is enormous, right up through the growth spurt of adolescence. And so appetite suppression in children can be a problem. And for that reason, weight monitoring should always be a part of prescribing psychostimulants. And in follow up you always want to have the patient's weight. And vital signs, it's not a bad idea to have them either. Because they are stimulants and they can cause a subtle elevation in heart rate and blood pressure, don't be surprised. Remember, in children tachycardia is the norm. The younger you are, the faster your baseline heart rate is. And even up through adolescence, it's not at all unusual for a baseline heart rate to be around 100. Throw in a stimulant, and that can crank up the baseline heart rate to like 110. So if most of your experience is with adults, that might catch your eye a little bit and you think, why is that happen? But in children, it's not unusual. But when the stimulant-- if the stimulant really does crank up their vital signs in an accelerated way, well, then that might be a reason to reconsider therapy and think about using 12 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... something else. So the takeaway message here is vital signs and weight should be recorded at every follow up when you are re!lling stimulants. The only real long-term adverse e"ect that has been documented that should be discussed with the family unit is that if we start stimulants prior to the growth spurt, and use them for the long haul, use it for chronic therapy, there may be a restriction of adult height by up to one inch. I mean, there's research to support this. I'm not entirely sure how they would know how tall the kid would be if they didn't take stimulants. But there is evidence to support that !nal adult height may be shortened by one full inch for the child who uses stimulants chronically beginning before adolescence or beginning before puberty. And while one inch might not sound like a whole lot, to many adults it really is. It seems like especially males, that one inch can make a huge di"erence. I mean, some people go through ridiculous surgeries to try to extend their height by one inch. So it is especially coming-- if the patient comes from a family that's got relatively short stature, it's certainly something that should be discussed with them. And the other notable bullet point here is that there is no documented relationship to cardiovascular events. Again, "When used properly" is the key phrase. If people are abusing these, there are those who will crush the immediate release ones, crush them, snort a main line and whatever. Well, then, yeah, of course, if you bolus yourself with a stimulant, there is the potential for a vascular event. But when used properly, cardiovascular events are exceedingly rare. This is another-- I'm going o" on a tangent here, I've got another thing worth mentioning. There is a trend in recent history to require an EKG before prescribing a stimulant. I mean, a number of prescribers do require this. And there is no evidence to support that routine 12-lead ECGs are necessary or helpful before prescribing a stimulant. What the literature says is that there should be a cardiac risk screening. So before you put anybody on a stimulant, you should be asking questions. Do you have any history of cardiovascular disease? Any palpitations? For children, did you have any problems at birth with your heart? Did the child have to have surgery on their heart as a kid? Like, you want to look for any cardiac history or any symptoms that are consistent with a cardiac problem. Like, for little kids, do they get out of breath really fast? Do they get out of breath faster than their friends? When they're all playing, do they always have to sit down and take a breath? Like, any cardiac symptom or any cardiac history, then a 13 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... 12-lead ECG is necessary to identify four undiagnosed cardiac problems. But if the history is benign and there is nothing in the history for concern, there is no evidence to support that an EKG is helpful or appropriate. And keep in mind every time you do any sort of diagnostic study, there is a chance of !nding a totally benign irrelevant variant, just a benign variant. But if you !nd something that is atypical, well then you've got to work that up, and it becomes a big mess. So the general rule of thumb, not just in psychiatry but in all aspects of medicine, is we only do a test when there's a clear indication for it. And in the patient who is a stimulant candidate, if there is no cardiac history and no cardiac symptoms, there is no clinical indication for an EKG. OK, so once you decide stimulants are the drugs for your patient-- oh, jeez, I mean dosing. Like I said, there's one for all occasions, short acting, long acting, ultra long acting. Just keeping in mind that any time you give a long acting drug, you have less control over it. But the clinical e"ect is going to be more steady. So what does this slide say? Numerous long acting and short acting forms exist, long acting forms lead to better tonic phase control. In other words, better baseline control. So if you have a patient who goes to school and they need to be on a stimulant for ADD. And they are consistently, every school day, having to take one in the morning before school and then they take a second dose like at lunchtime in school, which is really common, because-- excuse me-- they need that control all day long, every day. Whether it's a kid in school or an adult at work. If they are taking a morning dose and a noon dose every day, that's a candidate for long acting form. I mean, give them a long acting formulation, it's more convenient, they just have to take it once. They also have better tonic control. In other words, they have better stable control all day long. If you take a short acting formulation early in the morning, and then by lunchtime you have to take another dose, you're yo-yoing. You take your morning dose, it peaks, you're doing well. And then the levels start to fall o" and your attention is not as good by the time you take your next dose. And then you peak again in the afternoon, and then it falls o". It's like two hills. Like you start out in the morning, you climb up a hill, you get to the top, and then you start to go down it by lunchtime. Then you've got to take another dose and go back up 14 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... the hill. It's not consistent control. So for that patient, a long acting form it's more convenient, the control is more consistent. And, yes, there is a minimization of post dose euphoria because not only do the stimulates regulate dopamine and norepinephrine at relevant sites. But, remember, every time we give a drug, there is also going to be an unintended consequence. There's going to be action on other sites. And one of them is the sigma receptor. And the sigma receptor is another receptor hanging around the brain that is associated with euphoria. And when you give these medications, you also activate sigma receptors which produces euphoria, which is separate from ADD control. And it's what makes people feel good, and it's the reason they abuse drugs in general. Opioids are another class of medication that often produces post dose euphoria. So if you're taking it twice a day, you're going to get two times a day euphoria. And it's more tempting to abuse it. And so long acting doses are best. For people that need consistent all day long control, they're using it every day. So it's more convenient, it gives them a more level tonic phase control, and minimizes the-- let me try that again-- minimizes post dose euphoria. Now the downside is that if you get an o" day, maybe you had the chance to go home and take a nap, it's not going to happen. Or for patients whose routine isn't the same every day. Maybe their work routine is such that on some days they have to do certain things in the afternoon that really don't require the level of focus. So they don't take that noon dose, say, on Monday, Wednesday, and Friday. Well, then for that patient, a long acting formulation isn't a good choice. Short acting formulations allow them to really use it only when they need it. And so you have a choice to make. Some people are better candidates for short acting, some are better candidates for long acting. I mean, if you really believe that there's any possible risk for abuse, then a stimulant really isn't the right drug anyway. So that post dose euphoria isn't a huge driver for me. I mean, I don't give people stimulants, period, if I think there is the remotest possibility that they might abuse it. For me it really is about the type of control they need on a daily basis if their schedules $uctuate or if they are the same and consistent. So those are the considerations. 15 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... Now in terms of methylphenidates versus amphetamine salts, I think-- I mean, I already told you, they're more of the same than di"erent. I don't have much else to say here. Let's see, methylphenidates, yea, they regulate both neurotransmitters. I mentioned that Ritalin is the prototype one, but there's all sorts of other formulations here. Concerta is one of them. These do have rapid onset and shortest duration, even a little bit more so than the amphetamine salts. I mean, the di"erence is negligible, but these do hit the patient faster and metabolize more readily. So that may have some implication for you. And other than that, I don't know. I guess when I put these slides together I thought it was a good idea to give you all these brand names, but I'm really not necessarily advocating for one over the other. Just telling you what they are, and then you can make your options. Here's another one. Yes, vocal and very potent. I mean, this is for your really hardest to control patients. And then Cotempla XR is an early disintegrating tablet. So for people that-- some people really have trouble swallowing pills. I was like that, I couldn't even swallow a Motrin until I was like 45. So for people that really struggle with pills swallowing, you do have other options as well. So those are your methylphenidates. Like I said, both types, both methylphenidates and amphetamines, they come in all sorts of formulations. That alone really isn't the reason to pick one over the other. In the world of amphetamines, again, we have the prototype Adderall, we have short acting ones, long acting ones, ultra long acting. And, yea, they modulate the same neurotransmitters. And I think I mentioned this too, there is sort of an urban legend about the fact that amphetamine salts are more subject to abuse. I really think primarily because they have the word amphetamine in the name, and it just scares people more. But, really, there really isn't-- that's not a reason to pick one over the other. If you think a stimulant is the drug to use, then one of the things you are consider is, is this patient a risk for abuse? And if the answer is yes, well, that's the end of that, no stimulant at all. If the answer is no, then, well, amphetamine or methylphenidate, it's really just about, like I said before, what the patient has access to. For both drugs, not just Adderall, but for both Adderall and Ritalin. The short acting forms do appear to have the highest abuse potential, number one, because they can pop them orally several times a day to 16 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... get that post dose euphoria. But also these are the ones that lend themselves to crushing. And then crushing, they can be main line, they can be snorted. And all of this, of course, is more consistent with an abuse phenomenon. And, of course, in the same way that I gave you some branded examples of the methylphenidate, I feel compelled to give you some branded examples of the amphetamine salts as well. But I'm not going to separate over this. As I say, I'm not trying to sway you to one brand or the other. Just the real takeaway from the stimulant discussion that I really want you to get from this is that psychostimulants are the most e"ective medication for ADD. And that the two general categories of stimulants are methylphenidate and amphetamine salts. And that they really are more the same than di"erent. The only reason to pick one over the other is what the patient has access to. If their insurance will pay for one, well, then that's it. And if they have a problem with that one, whereas they do get symptom control but they can't tolerate adverse e"ects, or maybe they don't get good symptom control, but you're really convinced that it's ADD, well then, try the other one. And then once you deduce that a stimulant is the right drug for your patient, and you identify the stimulant one or the other, then the question is, do they need a long acting form or a short acting formulation? And the real reasons to use the long acting formulations are when they are consistently having to take a second dose during the day. It's just more convenient and more tonic phase control to give them a long acting dose in the morning and have it last all day long. The reason to use a short or immediate acting formulation is for the patient whose needs vary from day to day, and that gives you more of the ability to make those distinctions. And that's what the stimulant discussion is all about. Oh, and !nally, potential for adverse e"ects? Yes, appetite suppression, headache, in the long haul, growth restriction. And, !nally, the last takeaway message is everybody doesn't need an EKG. That's really more a manifestation of the litigious world in which we live where everybody is trying to sue you and everybody is afraid of being sued. So I do understand it, but truly, I mean, I have found and I do a lot of expert witnessing. I've been doing it for a very long time. I have over 100 cases under my belt. And I can 17 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... tell you that if you follow evidence and you document what you do, you really don't have a problem with respect to litigation. I've seen more litigation go in favor of the defendant than I have the plainti". And when that happens, it's always because the defendant nurse practitioner has followed standards of care. Or if you deviate from a normal standard, document why. So that's the stimulant conversation. Now let's look at the alternative, because we do have some other non-stimulant options. There are a few, a variety exist, to quote your handout. And, yes, the non- stimulant options, the likelihood of abusing them is almost nonexistent. Whenever anybody takes a pill for a long time for a condition, there is always the potential for psychological abuse because they associate the pill with feeling better, and don't feel well when they can't take the pill. So, I mean, there is always that. But in terms of actually abusing these, crushing them, snorting them, et cetera, obviously much less of a problem with the non-stimulant options. But the trade o" is they are not as e"ective. E#cacy, about 40% if you're lucky. So it certainly isn't the 70% of the stimulant options. But 40% is better than no percent. So, why would you use a non-stimulant option? Well, funny you ask, here you go. Typically non-stimulant options are used in three circumstances. A, you are concerned about the potential for abuse, B, the patient has tried a stimulant, but really can't tolerate the adverse e"ects. This de!nitely is the exception rather than the rule. But, yes, there are people who get really bad headaches or they just can't sleep or they get tremulous, or whatever. They can't tolerate the adverse e"ects, and then they need to go to a non-stimulant option. And then some people just don't want to be on a controlled substance or they don't want their children on a controlled substance. And if that's the case, well, then you can't use it. So when you make a diagnosis of ADD, the important thing to remember is the stimulants are the best medication for it, the best treatment for it. The only reason not to use a stimulant are these things that are listed here. And so it becomes a conversation with the patient and the family unit. If you decide that a non-stimulant option is the way to go, you really don't have a lot of choices, you have a few. And I'm being representative here. There's new drugs emerging in each class. So it's always really about what's on the formulary of the 18 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... patient's insurance company. But the next class of drug that's a non-stimulant option is the norepinephrine reuptake inhibitor atomoxetine, which is marketed as Strattera. Now, again, there's other norepinephrine reuptake inhibitors on the market now for ADD. I think the last one I saw is called Kelby. And I'm sure there's something a little bit di"erent about it. Like I said, any time you have a !rst drug in class, it passes FDA minimum safety and e#cacy requirements. But there's usually some adverse e"ects that are at least uncomfortable or undesirable. And then subsequent companies will try to !nd a way to make that better. So Kelby may de!nitely-- I don't have any experience with it so I can't tell you about it !rsthand. But Kelby may de!nitely have some edge on Strattera. But they both have the same mechanism of action. And it's described here. Notice, number one, these are purely norepinephrine reuptake inhibitors. So dopamine is not in the picture. There is no impact on dopamine, which, of course, explains why they're not as e"ective. But, yes, they tend to be very well tolerated. People don't abuse them, nobody's trying to score any Strattera in a back alley or use it to get high. But the response rate is less impressive, 40%, 70%. You can do the math. And because norepinephrine is the primary treatment target, the primary utility in these drugs are in the patient who can't !lter out the background distraction. This is why you will have some people tell you it's great, it's really helped, they're doing much better. And then others will tell you, no good, not helping at all, no point in taking it. For the people-- and the people for whom it is really helpful, clearly their primary problem is norepinephrine dysregulation. And the people it doesn't help at all, well, their primary problem is probably dopamine dysregulation. So if you put it on somebody because you don't want to use a controlled substance, and they come back and say, this isn't helping at all. It's not necessarily that they're drug seeking, it might just be that it's not helping. And then another important thing to keep in mind here is patient education. If you deduce that you cannot use a psychostimulant or the patient doesn't want to use a psychostimulant, you want to be really certain that they understand that the response rate with other options is not going to be as good. I mean, 40% is better than no percent. So if it can give them any assistance in controlling symptoms, de!nitely worth 19 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... a try. But especially people who have taken stimulants in the past, like somebody who was on Adderall before, and maybe they abused it, and that's why you're not going to use it again. So when you o"er them this, you want to be clear that they shouldn't expect the same outcome. It's just not going to be the same. But like I said, 40% is better than no percent, so why not. Another option we have in the non-stimulant category are the Alpha 2a Receptor Agonist. These are anti-adrenergic agonists. And the two general groups of them you see on your hand out here are guanfacine and clonidine. Guanfacine very popular for children. People that are medicating kids with ADD often want to start with guanfacine. Tenex is the short acting version, intuniv is the longer acting version. And then clonidine-- and, yes, this is the same clonidine that we use for blood pressure control-- this is another alpha 2 receptor agonist. And it's used o" label for ADD. So these drugs directly activate anti-adrenergic responses. Anti-adrenergics, so these are anti-adrenergic agonists. And norepinephrine is one of the neurotransmitters of the adrenergic system. And basically giving guaifenesin or clonidine activates a response that blocks norepinephrine action, if that makes sense. The short version here is that these really also are just about attenuating the norepinephrine problem. There's no impact on dopamine. So, again, not going to be as helpful. These do tend to cause some level, really, of-- what do you call it? Like sedation or calming. Sedation is a little bit of a strong word, but that's what it does. And so that's why it can o"er some improvement in hyperactivity and impulsivity. But the actual ability to stay focused-- remember the rabbit ears on the TV, you're not going to get that with these drugs. It just doesn't increase attention. So if the primary problem really is the kid just can't sit still, and they're just blurting out answers before the teacher even asks a question, try it, you can try it. But, again, it's always about advising the patient and the family that the utility is just not as strong. Better than nothing, but just not as strong. But because they're not controlled substances and because they're approved in children, they do tend to be a popular favorite, especially in the primary care setting for kids with ADD. So that's that. 20 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... Now another o"-label option-- and this is o"-label is bupropion. Bupropion, you might recognize this from our antidepressant discussion. Bupropion is Wellbutrin. It is marketed as Wellbutrin and used for patients with depression. Remember how it works, right? It is a dopamine reuptake inhibitor. And it actually has a little bit of a norepinephrine piece there as well. But primarily this is a dopamine reuptake inhibitor. It doesn't appear-- I mean, it's just not as profound as a stimulant. It certainly isn't just as powerful as a stimulate-- stimulate, as a stimulant. But because of its actions on dopamine and norepinephrine, it's a reasonable try. If the patient can't take a stimulant, this is something that you can try. Again, it's not going to give you that same 70% e#cacy. But if you can't use a stimulant, you get 0% e#cacy. Try bupropion, maybe you'll get a 30%, 40% e#cacy. Primarily you will see this used for people that seem to have depression and ADD as comorbid conditions. So that's another option. Don't expect a lot from it, is what I'm trying to say. And then the last one in this slide, so the last discussion here are the wakefulness agents, moda!nil and armoda!nil. You might know these, they are marketed as provigil and nuvigil. These were originally designed for people with narcolepsy. These keep you awake. And then they've had some expanded indications for sleep work or shift disorder, people who work rotating shifts and stu". And they are also used o"-label to enhance focus. These are-- no, I don't know if this is true or not. I know if it's urban legend, so I have to disclose that. But I have also heard that they are used in the military for pilots, and people with those sorts of roles that are awake for extended periods and have to be highly focused. So how it works for ADD is unclear. But it de!nitely appears to be more about the focus than the hyperactivity and impulsivity. These drugs really do help people stay focused. I have found them to be very e"ective in people whose primary problem is like the dopamine dysfunction. The adverse e"ect pro!le, really minimal. We just don't know yet. I mean, the worse part of it is about keeping you awake at night. When you have the opportunity to sleep, you just can't. So there's a patient education thing there in terms of if you're going to take this, it's got to be !rst thing in the morning. Don't plan on sleeping until night time. And it is a controlled substance. I think they're Schedule IV or Schedule V. Probably Schedule IV, I don't know. It's de!nitely among the more benign controlled substances. So providers sometimes just feel better giving this as compared to a stimulant. But I 21 of 22 6/26/24, 9:37 PM Stimulant and Non-stimulant Medications for ADD Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... found it to be extremely e"ective in patients for whom the primary problem is the inability to stay focused on task. And so that is yet another option. It still used o"-label but many things we use are o"- label. And actually when we talk about the legal aspects of practice, you'll see that o"- label is very legal, and that's why it's something we do very often. But from the world of a stimulant and non-stimulant medications, that's what I've got for you for this hour. So use this and supplement it with your other learning activities. And so that you can go on and master your assignments for this week, and get ready for that !nal exam. Print this page 22 of 22 6/26/24, 9:37 PM Pharmacologic Management of Sleep Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... Pharmacologic Management of Sleep So this week one of our topics of conversation is pharmacologic management of sleep. Insomnia, very common problem. We do have several options in terms of treating it, and there is a model of the pathophysiology of insomnia. And so normally, it's typically my MO to !rst look at the physiologic abnormality that produces symptoms, and then we analyze our drug choices with respect to what is the pathophysiology. But with sleep it's a little bit di"erent. The thing with sleep disorders is that we do have multiple things that can cause insomnia. In fact, insomnia itself is a term that could mean many things. But when we look at the model of the pathophysiology of sleep it is truly multimodal. There's lots of things that can conspire to make a person have trouble sleeping. And so normally we would say, OK, let's isolate the problem for you and then pick the best drug for that problem. But the pharmacologic management of sleep is not that way. With sleep disorders, we have a series of medications, we have several options, and we have a typical trajectory. In other words, X drug classes, the !rst thing we use. And if that doesn't work, we either add this other class to it, or maybe change classes, then we have a third line class, and then we have a series of steps. And it's what we do regardless of the pathophysiology. So the di"erence between managing sleep and managing another disorder is that even though we recognize that there are multiple contributors to sleep disorders, that really doesn't in#uence our choice of medication. Once we deduce that somebody needs drug therapy to help them sleep, we're going to look at our steps and start with step number one. And if that doesn't work, go to step number 2, 3, 4, et cetera. The reason that it's helpful to understand the physiology of sleep disorders is not that it's necessarily going to help us distinguish one drug from the other, but it helps us understand why some people respond very well to certain meds and other people don't respond at all. With sleep, it's not unlike some other disorders where some of the drugs we have to manage it are controlled substances. And we just live in a world 1 of 20 6/26/24, 9:37 PM Pharmacologic Management of Sleep Transcript https://alt-5c5afaf83f339.blackboard.com/bbcswebdav/pid-2425030-dt-... where controlled substances are like they're evil. I mean, it started with the opioid crisis. And now with benzos and sedatives, we just really see a resistance to prescribing controlled substances. And so, very often prescribers will prescribe anything that's not a controlled substance just because we don't want to prescribe controlled substances. And I'm sure there's a happy medium. Some people go too far in one direction, some too far on the other. The truth is that controlled substances are necessary medications for some people, some people really need them. And so in some circumstances it is appropriate to prescribe them. When it comes down to sleep disorders, we have controlled substance options and not-controlled substance options. And the thing is, is that sometimes you will !nd among your peers they will start with the non-controlled options just because they feel more comfortable doing so. And when the patients come back and say this didn't help, it didn't make any di"erence at all, I'm still not sleeping, it's not working. Sometimes there's a tendency, there's like an implicit bias to say, oh, they just want the controlled substance, they're just drug seeking. And look, I can't say that never happens, but I can tell you that sometimes it's true that the non-controlled substances just don't work, sometimes the patient will need a controlled substance option. And I say this as a preface because as you go through this discussion and you look at the pathophysiology of sleep, you'll begin to understand how there are multiple things that can conspire to produce insomnia. And one particular issue may be the primary problem for X patient, and that patient will respond very well to a non-controlled substance, and it's awesome. And then another patient, the primary problem might be something di"erent. And the drug that works so well for patient A won't work for patient B. And so I think understanding the physiology of sleep disorders, it's not so much that it drives our choice of medication, our choices really don't change, but what it does do is give us some understanding of why perhaps certain agents don't work for certain patients. And if that doesn't make any sense to you at all, don't worry I think as you go through

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