Okay class, this is the week 12 wrap-up that is covering ADHD medications. And so this is just kind of tying together the content that comes from the exam study guide for exam 4, and then for the content that's covered in the weekly learning objectives. Some of this is not going to be covered. like the legal ramifications per se, because that's not really going to be tested, since that would vary to some extent by state to state, so we can't really account for that on an exam, given that people will be taking it from different states, but all the other things we'll kind of address accordingly.
So like we've done in other lectures, like psychosis and for depression and anxiety, it's always helpful to sort of break the syndrome down into symptoms and then connect these symptoms to brain pathways and neurotransmitter actions on those pathways to sort of get an understanding. So the major categories of ADHD basically divided into really three parts of this pie. So you've got inattentive symptoms, hyperactive symptoms, and impulsive symptoms.
And then inattentive could be further divided into selective and sustained inattention or attention problems. And so this is connecting the different parts of the brain where this symptoms theoretically are tied to. So for selective attention, you've got the dorsal anterior cingulate cortex.
With sustained attention, you've got the dorsolateral prefrontal cortex with hyperactive symptoms, that's that prefrontal motor cortex, and impulsive symptoms is the orbitofrontal cortex. And so it's interesting how over time ADHD tends to morph and kind of look different. I think this is by and large why it can be very difficult for ADHD to be diagnosed in adults, because it will look very different than how ADHD presents. during childhood.
So if you're looking at this graph, you can see how initially it's kind of the impulsive and hyperactive symptoms that are problematic in preschool or young children. And you know, that's by and large what gets the most notice from adults, from teachers, from parents. And so During the school age and childhood, it's that hyperactivity, impulsivity that seems to be the most prominent as far as symptoms go. But then you notice how inattention increases from then on. And so with adults, that tends to be more of the issue that comes up.
You're not seeing so much of the impulsivity and hyperactivity in adults. So it's interesting how over time the hyperactive impulsive symptoms will decrease, whereas the inattentive symptoms stay pretty constant and are the most prominent symptom as the ADHD patient ages. So circling back though, just to reiterate, with sustained attention problem solving, that takes place in the dorsolateral prefrontal cortex. You know, you can test that with the INBAC test. You don't really need to know that, but that's one way to remember it is that sustained attention with the N back test.
And then the selective attention is in the dorsal interior cingulate. So you can kind of remember selective attention cingulate, kind of that play on the sound of that S. Selective cingulate. And with the orbital frontal cortex, that's where impulsive symptoms come from.
So, you know, hyperactivity and impulsivity, of course, are very much, they go hand in hand, okay? And to some extent, it's modulated by the corticostriatothalamic cortical loops, the CSTC, which we learned about with anxiety. But there's, you know, limbic actions of the orbital frontal cortex and then motor kind of actions.
And so, but don't get that confused though, because the hyperactive symptoms are occurring in the prefrontal motor cortex. And so this is really all kind of just saying the same thing. Okay.
So these are just different ways of looking at the same thing that we've sort of just mentioned, but ultimately the... Problems with ADHD come down to like a tuning issue. It's not so much like a deficit or an excess issue as much as it's sort of getting on the right station and then having a strong signal, kind of like with a radio if you're driving in the car.
And this is another way of kind of looking at that because if you have too little of norepinephrine and dopamine, and these are really the two main neurotransmitters with everything that's related to ADHD, these are our two key transmitters. With too little, you sort of have issues with being distracted and disorganized and forgetful, you know, fatigued. But then too much can look like mania or it could even look like psychosis. And so that tends to, it could even look like panic attacks even. So it's like too much is not good, too little is not good.
So there's this sort of optimal amount on this bell curve, as you see, where you've got enough. norepinephrine and dopamine activity through the alpha 2a and d1 receptors. So this is another way of kind of looking at where if you have poor signal but high noise, and we'll talk about this on another slide, you know that will kind of affect things in one way whereas if you have an optimized level of the norepinephrine and dopamine as far as the signaling and the noise ratio goes, then it corrects those symptoms as you see of kind of like the hyperactivity. So this is kind of explaining what we're talking about when we're talking about noise and signal.
So norepinephrine helps make the connections. increases the incoming signal and allows for increased connections between that prefrontal cortex and all those networks and it does that through stimulation of alpha 2a receptors okay so you can kind of remember it as they're sort of like the old-timey telephone objers they increase that signal and they and it makes the connections you know more strong whereas dopamine prevents inappropriate connections from taking place and it decreases the noise. So it's kind of like this librarian that shushes things.
So that's kind of the actions that these two neurotransmitters play here. And let me go back one second. So this is talking about tonic firing. And so under normal conditions. You would want, you know, a little bit of tonic firing because that can help as far as like working memory and learning go, but too much of that can impair it.
And you'll see that more so like with phasic. I think I might have misspoke there. Under normal circumstances, tonic firing is how it's supposed to be. Phasic firing is what, if used in moderation, you know, it can help with... incremental learning and memory, but too much phasic firing can actually lead to erratic, like pleasure-seeking activity, and that's where addiction comes into place.
So we'll learn how, depending on the formulation of a stimulant, it can enhance tonic firing, which is more kind of what we think is normal, versus enhancing phasic, which can be a potential problem. So Long-acting or slow-dose stimulants, that's how Stahl kind of talks about them, they amplify tonic norepinephrine and dopamine firing. So that's, again, how it should be normally.
And they do so by blocking norepinephrine in the prefrontal cortex and the dopamine transporters and the nucleus accumbens. The nucleus accumbens being very much an important factor in kind of reward and addiction. So the slower stimulants or the long-acting stimulants will occupy that norepinephrine in that prefrontal cortex slow enough and long enough that they enhance that tonic norepinephrine and dopamine signaling, but they don't do it so quickly or potently that the phasic signalings increase in that nucleus accumbens.
And it's because of that, because they don't sort of stimulate potently and quickly that phasic signaling in the nucleus accumbens, that they theoretically are less likely to be abused or misused. because you don't get that sort of quick fix, which is what the nucleus accumbens wants in the sort of process of addiction, which we will talk about in other lectures. So short-acting stimulants, however, or immediate release formulations, they will lead to very quick, potent bursts of dopamine. And again, in moderation and sort of in controlled ways, that's actually a good thing.
It helps reinforce learning and reward, helps with motivation, but too much of that is not a good thing, and it can sort of become out of control. And that's where that reinforcing the reward of... misusing substances can come into play and that whole reward circuitry gets hijacked and it sort of exacerbates the impulse and the impulse control and turns more to compulsive seeking out for that substance and this is just another way of saying that so pulsatile or phasic stimulants which tend to be short-acting immediate release options lead to increased basic firing which is at increased risk for misuse and abuse of substances whereas tonic or slow acting stimulants not as risky just one more way to kind of look at what i've said a couple of times so so then um it's not unusual of course for there to be a lot of overlap in diagnoses.
It's kind of unusual, actually, for there to be just a pure one diagnosis patient. It happens, but it's not common. So then what is it that you're supposed to do first when you have a patient that presents with a variety of comorbid conditions and also has ADHD? Well, STAL kind of gives you this hierarchy of treatment planning. And so obviously with any kind of psychiatric diagnoses, if a person has active substance use or dependence, you really can't even diagnose anything else until that is treated and no longer in the picture.
Because as long as it is, all of the symptoms or problems can sort of be tied back to the substance use or dependence. So you've got to treat that first and then sort of move down by there. So how do we treat ADHD? Well, we already know that ADHD is a disease.
Problem of the tuning with norepinephrine and dopamine in their respective parts of the brain, prefrontal cortex, nucleus accumbens. So all of the ADHD medications are going to work on norepinephrine and dopamine to some extent. So fortunately, that really doesn't give you too many treatment options. So I guess that's good compared to a lot of the other disorders you've learned about. This is actually pretty easy pharmacologically.
So you basically have two families of pharmacological options. You've got Adderall or you've got Ritalin. Adderall or really amphetamine-based medications work by increasing dopamine and norepinephrine.
And so they do this by... Sort of this variety of pathways as you see. So there's a lot of steps to this, but basically when you take amphetamine, it's going to competitively inhibit the dopamine transporter, kind of like we have serotonin transporters that the SSRIs work on. So that's one action that it does is it competitively inhibits that part.
It also works here on VMAT. And it is taken up into the dopamine terminal via this dopamine transporter here. And it can be packaged into vesicles. And at a high enough level, it basically will displace dopamine from those vesicles and into the terminal. So basically, it will directly lead to the release of dopamine.
So that makes it very different in many ways from how Ritalin works. And we'll talk about that in the next slide. But basically, amphetamine works on the dopamine transport directly. It also affects VMAT, but it directly leads to the release of dopamine by displacing those dopamine molecules from the vesicle sites. Whereas...
Ritalin, it works kind of like an SSRI. It works by blocking the reuptake of the dopamine transporter and by blocking the norepinephrine transporter and by sort of Keeping it stuck there, it leads to increased availability of dopamine in the synaptic cleft and as well as norepinephrine in the synaptic cleft. So it does not get taken up by these transporters like amphetamine does. It doesn't work on VMAT, as you see.
And it does not lead to direct release of either of these. It just makes it more available. Okay, so...
I like this slide. It gives you just kind of the general likely side effects of stimulants or ADHD treatment. We won't really talk about, in this lecture, sort of off-label uses for antidepressants in the treatment of ADHD. We're just going to focus on FDA-indicated treatment options for ADHD.
So you've got stimulants. Again, it's going to be ritalin or Adderall, amphetamine or methylphenidate, and then you've got the non-stimulant Stratera. So you'll want to know kind of what would be the...
commonly expected side effects of these medications. That way, if a patient reports a side effect and asks, do you think it's the med? You would know if it's likely to be related to the medication, or if it's likely to be something different that's, you know, not related to the medication.
So this comes literally from a package insert for, I think it's Adderall XR, but this would apply pretty much to any stimulant, okay? So these are the sort of warnings and precautions that are listed. by the FDA in the black box warnings, which is not listed here.
But you definitely want to be careful with stimulants because there is this risk of sudden cardiac death in children or adolescents with structural cardiac abnormalities or other serious heart problems. There have been other sort of cardiovascular and neurological events that have happened in adults taking stimulants. And so it goes without saying, I guess, that if you have a patient that has a known structural cardiac abnormality, heart disease like cardiomyopathy or some kind of serious heart rhythm, coronary artery disease or other really serious heart problem, you probably shouldn't use a stimulant, right?
Stimulants can increase blood pressure, which we will talk about the degree to which they usually affect blood pressure. But this is one reason why we always monitor blood pressure. pressure impulse when we are treating patients with stimulants. Of course, if someone has underlying bipolar disorder, a stimulant can make that much worse.
So again, if we were to go back to that one slide, and that sort of talks about the hierarchy of treatment goals or sort of what to treat first, you know, after substance use, it would be mood symptoms. So that either be depressive or manic symptoms. have an anxiety symptoms and then you go down to kind of ADHD. Again kind of tying back to cardiac and cardiovascular related it's interesting how with stimulants you can get like renonce phenomenon kind of emergent from that. I don't see that often but I have had patients report that before.
It's I would say this is a fairly rare thing but it's one of those that like if someone reports it, you should know that it's related to that. So it's uncommon, but it is possible. Ticks, of course, stimulant can exacerbate that.
This also comes from the package insert and talking about, this kind of just reiterates what's on that first slide there. And so this is really more what I wanted to talk about here is hypertension and other cardiac conditions. And on that other side, it did talk about how we monitor blood pressure because it can affect blood pressure and heart rate. So notice here though, how it says stimulant meds can cause a modest increase in the average blood pressure. So like two to four millimeters of mercury here, and it has a modest increase on the average heart rate.
Now we're talking like three to six beats per minute here. Now of course there are some individuals that might have larger increases because again we're talking about averages so of course there'll be some that have much less and some that have much more but you know while these average changes alone wouldn't really have any major consequences you want to watch over the long term if there were any greater changes in heart rate or blood pressure. So this here just is like a snapshot of Basically how blood pressure is affected in stimulants or by stimulants in children and adults. And so you can read this in more detail, but it's basically going to reiterate what the package insert says here.
So generally speaking, you would not expect stimulant medication to have a huge impact on blood pressure. That doesn't mean that it can't, but you wouldn't expect it to. OK.
And so if the package insert is telling us that we should avoid it in children with known, you know, structural cardiac problems and whatnot, like how would we know that? Well, with any body that you're going to put on a stimulant, it's very important that you do an assessment. And that entails, you know, really getting a good history. So with children, of course, you'd probably need to have a parent there because they're going to have a much more more reliable history than a child's going to, or maybe even an adolescent or a young adult. So history is very important.
So if there's a family history of sudden cardiac death or serious ventricular arrhythmias, that's going to be a problem. You know, if in your history taking, there's anything that would lead you to be concerned for the possibility of such a disease, then it would make sense to refer for sort of cardiac. clearance or additional workup, which would entail an EKG.
And of course, if while on a stimulant, a patient starts complaining of chest pain or they pass out or any kind of cardiac stuff, then that too should prompt you to refer them for a cardiac workup. The summaries and recommendations here, which comes from UpToDate, I think it's important to point out that while there are concerns about the cardiac effects, stimulants alone don't seem to increase risks of cardiac death or heart complications in people who don't have underlying cardiac disease. So it's not like the appropriate use of stimulants in an otherwise healthy individual will lead to cardiac problems.
And it also just reiterates that the effects on blood pressure and heart rate are relatively small. three to ten, three to nine beats per minute. The systolic blood pressure is like three to eight millimeters of mercury, the diastolic is two to fourteen.
And so there has been some controversy in the past about whether everyone who's on a stimulant should get a EKG or whatever, but the current guidelines do not recommend getting a baseline EKG before starting a stimulant for patients with ADHD. Of course, unless there was known cardiac disease or the history-taking process would lead you to be concerned that there might be, well then of course you shouldn't prescribe a stimulant until that's sort of ruled out. So bottom line, in healthy individuals, there's not going to be an increased risk, so you don't need to get a baseline EKG. So this is talking about Stratera, moving over here to the non-stimulant options for ADHD.
And there's only three FDA-approved non-stimulant treatment options. So Stratera works by blocking the norepinephrine reuptake, and by doing so, it increases norepinephrine and dopamine levels on that prefrontal. cortex.
Now it does it slower, so it does not do it like an immediate release stimulant, and it doesn't do it immediately even like a long-acting or slow-release stimulant. So because it doesn't lead to a rapid flooding, if you will, of dopamine into the nuclear accumbens, it's not really a risky drug for abuse or misuse. So that's good to know. But it does help in that prefrontal cortex with the tuning process of getting the right levels of norepinephrine and dopamine there to where it helps with the inattention and decreases hyperactivity without the risk of like reinforcing because it doesn't have any action there in the nucleus accumbens.
With Stratera, it's going to have very similar side effects as a stimulant, it's just much weaker so. Kind of interesting things to think about or know about with Stratera is there's this very rare, thank goodness I've never seen this happen, but it can cause severe liver injury. So when you think of Stratera, think of kind of liver-related stuff.
It also can have some drug-drug interactions. Ritalin and methylphenidate really don't have. hardly any drug-drug interactions as far as pharmacokinetic reactions are concerned. But Stratera, on the other hand, can, because it is very much metabolized by this cytochrome P452D6.
So there are definitely drugs that we would use in psychiatry that can be very strong inhibitors or strong Inducers. Inducers you're not as worried about because all they'll do is just lead to decreased levels of Stratera. So then that would mean you would need higher than normal doses. It's inhibitors that you kind of get concerned about because they will increase your Stratera levels, which could lead to much more side effects. So notice you've got our big three that go through 2D6 are Paxil, Prozac, and Welbutrin.
Paxil-Prozac-Balbutrin. And here are our non-stimulant options. So these work on Alpha-2a. And remember, when we go way back earlier in this slide deck, we were talking about the noise and the signal and how norepinephrine helps strengthen the connection and the signal through its action on Alpha-2a receptors. This is why guanfacine and clonidine have a role here.
They tend to be much more helpful on the hyperactivity symptoms, not as much on the attention part, but they help sort of tone down that hyperactivity because of their action on the alpha-2a receptors here. So when would you use one over the other? Well, if you just look here, clonidine, I like to think of it as just a messier drug because notice how it works on much more... receptor sites than just alpha-2a.
So because it's a so-called dirty drug, it's going to be more likely to have side effects like the sedation, hypotension, dry mouth, things like that. Guanfacine, since it's, we'll say, a cleaner drug, I guess, and it seems to more purely work on alpha-2a, it's not going to be as likely to... have some of those other side effects like sedation, blood pressure, lowering, or dry mouth.
So it generally is more tolerated, or it's better tolerated. Just a fun fact, if you administer guanfacine with a high-fat meal, its absorption is very much significantly increased. So you want to advise patients about that.
So this is just kind of a summary. about the non-stimulant options. It gives you some dosing information on that, which the exams don't ever test you on dosing, but it might be useful just for your own interest there.