Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk, Episode 93 I'm your co host, Dr. Kane. Speaker 1 00:34 I'm Dr. Schuman, and today we're going to introduce episode 93 focusing in on ADHD treatment, and this is a chance, really, to go through and discuss a little bit about stimulants and other medications for each treatment of ADHD. After decades of use, technology has resulted in changes in how they're administered and the different dosage forms that are available. There's newer agents, but really are they an improvement? And a chance to kind of look at even how the history of the diagnosis has evolved a Dr. Sean Kane 01:01 bit over time. And Dr. Schuman, just for time purposes, as I understand it, we're going to focus mostly on the stimulants, knowing that there are other non stimulant medications out there. We'll kind of touch on it a little bit, but maybe that would be something ripe for a future episode, but maybe not today. Speaker 1 01:14 Certainly, there's actually so much just on the stimulants alone that I think it'd be a massive, massive, Super episode. And so we'll kind of break it up a Dr. Sean Kane 01:22 little bit. So why don't we start with just, you know, the definition of ADHD? I think that it's one of those things that people kind of casually, jokingly say, Oh, I've got ADHD today. Clearly, this is a medical diagnosis, right? So what are some of the things that play a role in that diagnosis? Speaker 1 01:35 Correct? And so the big thing again, is you have the attention deficit hyperactivity, and then there's also add, without the hyperactivity, but just the attention deficit. We're really going to focus on the ADHD component. And so again, that we have the Diagnostic and Statistical Manual (DSM-5), which is the gold standard for the listing the diagnostic criteria for for mental illness, and some of the things that mentions, you know, a persistent pattern of inattention and or hyperactivity impulsivity that interferes with functioning or development. And the big thing, again, with with how mental illness and psychiatric disorders are classified, you know, the pattern, the word then and the interference are two things that pretty much every diagnosis needs, somebody that has symptoms of anxiety or has attention difficulties. It has to be a pattern, and again, it has to significantly impair their ability to complete their job, to go to school and to be able to function. Dr. Sean Kane 02:28 So then I assume, because anytime I look at a DSM criteria, it's a very big list, and then you have to meet X number of items in that list, I assume the ADHD is similar Speaker 1 02:38 to that. Yeah, for example, with inattention. There's six symptoms they need for a six month period, or only five of them, if they're older than 17, and just a couple of ones to rather than go through the whole list, they're distracted, forgetful, avoiding tasks that require sustained effort, difficulty following through, not paying attention, difficulty, kind of, staying focused on activities. And then also, there's a hyperactivity piece. And again, you need a certain number of symptoms, six, if they're a child, or five, if they're older than 17 years of age, within a six month period. So this is not a diagnosis that can be made in just a one month period. And that hyperactivity things that, again, we, I think stereotypically, think about fidgeting, moving around the classroom, restlessness, talking, excessively, blurting out answers Dr. Sean Kane 03:23 and just to clarify then. So for adult onset ADHD, most of these patients will have had symptoms when they were younger. They weren't diagnosed at an earlier age, but they did have some characteristics consistent Speaker 1 03:34 with ADHD, yeah, and again, a lot of times. And that's, you know, this can be misdiagnosed. We think about anxieties, or somebody that can have inability to sustain tasks requiring attention because their mind is racing, whether it's due to substance use, bipolar disorder, PTSD anxiety and so to be careful of those things as well. Dr. Sean Kane 03:52 So you know, I don't see pediatric patients, but I do see pharmacy students a lot, and I think that in pharmacy school, and I would assume with other graduate level degree programs, especially in the medical field, given the strenuousness of the program, it's not uncommon that I will know about a student that has newly diagnosed ADHD that kind of comes out during pharmacy school. Can you just briefly explain, like, have you seen that as well, and what are some of the symptoms that kind of crop up that make that a thing that gets diagnosed in pharmacy school, as opposed to when that person was 12 or Speaker 1 04:25 five years old. I think one of it is, again, is to an extent, you know, a lot of times individuals who do very well and are higher performers have may be able to skate by, for example, with less than ideal study habits. Or, you know, certain ways they've been kind of able to cover up, and then you get into an intense graduate school, and some of those traits may may not be working as well, the ability, or you're also now working as well. And so maybe we're before you're able to say, like, you know, I was put in the quantity of hours, but not the quality, but now the hours are down because I've got all these other competing interests because of that. You know, only have x number of hours, but I'm not as focused in those and I never really was. I just needed the extra time. Now I don't have that. So I'm suffering others. There's more stressors and things like that that come up in life. And so yeah, for those reasons, it can be difficult, and it may take somebody then to re examine diagnostically as well as what you're doing. And that's where we have our, you know, our counseling center and testing center and testing center here to be able to help with individuals, to be able to develop study habits and things like that Dr. Sean Kane 05:25 as well. And as I understand it, you're going to have some of these symptom characteristics. But there's other criteria that you have to meet in order to say, yes, you have ADHD. And a great example of this would be there are certain environments that you sit next to the class clown and you just can't maintain attention because of this external thing going on. So what are some other criteria that come up? Yeah? Speaker 1 05:43 So one of the ones, yeah, is, again, it has to be noticed in two or more settings. So it can't just be home or work or school, and so there's gonna be situations where there's parental conflict, or maybe there's abuse in the home, or there's another factor to where a child just is acting out at home, and but it's not due to ADHD and vice versa. If there's a conflict just to teach or a bad, you know, teaching style, something like that again. So where it's fine in one or better, but not in the other, it's to pick up on those factors. So it really needs to be in those two or more settings. And that's where there's, you know, parent rating scales and teacher rating scales as well, to be able to do that. And then, as I mentioned, interference with quality of life or functioning is a big piece of it, and then not caused by another diagnosis. Those last two are standard across the board. For any kind of psychiatric diagnosis, you have to be able to show that it really is addressing affecting quality of life, and you have to prove that it's not due to substance use, substance withdrawal or another better explained by another psychiatric illness. Dr. Sean Kane 06:35 As I mentioned at the beginning of the podcast, ADHD is one of those things that people kind of bring up as like, Oh, I've got ADHD today. You know, there's a lot of truths and myths about ADHD related to the rate of ADHD. And you know, what are some causes of that? So, very briefly, what are some things that come to your mind when ADHD comes in the lay press? So I guess Speaker 1 06:54 there's a couple of kind of, I think, of truth versus myth. One of the big ones is the idea that ADHD rates are increasing with drug companies leading the way. That's been one that's come up for a number of years. So to look at it, Polanczyk et al. (2014) reviewed 154 eligible studies over 1985 to 2012 and the diagnosis has evolved over that time period. So they looked at a wider course, and they looked at prevalence using a multivariate model, and they found that the differences in prevalence rates across those studies, it was really due to the source of information. Were they getting it from the teacher? Were they getting from the parents, things like that, that maybe if you ask only teachers, the rate's going to be different than just asking parents in these prevalence rates. And they also looked at whether impairment was needed and what the diagnostic criteria used were they found that those were the things that affected the prevalence rates and its fluctuation over time, geographic location and then year of publication did not appear to be influencing rates. So what country you lived in and what year the publication was did not seem to be affecting it. So that kind of pushes against the idea that the rates are increasing if there's other factors that influence why one study may be higher or lower than another. Dr. Sean Kane 08:03 So you're suggesting that it matters who is being surveyed for ADHD. It depends on different diagnostic criteria, and that may alone be implicated in why ADHD rates appear to be increasing, but maybe aren't truly increasing. Speaker 1 08:18 Yeah, and you can see some of the variance in the prevalence to the CDC does a really nice job of putting out a table that kind of goes through and shows them the prevalences, but they also make sure to put in there when did each change in the diagnostic criteria occur? And we're going to go ahead and hyperlink that in our show notes as well, so listeners can can take a look at that. You know, yes, in the 1970s only 6% of individuals were diagnosed, but that was using this term called hyperkinetic reaction of childhood in the DSM two and so that wasn't even before add with and without hyperactivity. So you can't compare that and say, Oh, it's gone up, because they weren't even looking at the same things back then. Perfect. Dr. Sean Kane 08:54 Now another either myth or truth, that I've heard is that ADHD rates are more prevalent in the United States, or at least in the Western world, as opposed to other countries. What can you Speaker 1 09:04 say about and so again, back to that article I mentioned before. What they found is prevalence rates are similar among North America, South America, Australia and Asia. Location only mattered in the in the Middle East and Africa. But even there, they said it was because it was much, much less data. So it was a little bit you get a rounder pool of data in other countries that may kind of that may kind of smooth out some of the inconsistencies. Dr. Sean Kane 09:25 And I feel like this comes up a lot because proponents or opponents of ADHD treatment say, Well, maybe our children have more ADHD because of more TV or iPads or whatever. And it's really easy to have this poor argument same cause and effect, where maybe it's not even different period, but even if it was different, you can't necessarily say it's an association versus a causation problem, correct, right? Speaker 1 09:48 And one of the things you know, another kind of truth versus myth is yet about poor parenting that kind of goes into that, is it's just that, well again, if you if you weren't doing this thing with the iPad all day, well, you wouldn't have your problem your kids or something like. It. Some studies have shown that a non authoritative parenting style or lack of coping skills on the part of the parents are related to ADHD exacerbations. But again, the data is really inconsistent. In looking at that piece, one study did show association between combined‑type ADHD and inconsistent maternal discipline. So there is a little bit about discipline style that I think parents may want to be aware of in how, you know, engaging kids. But again, as you mentioned, it's way far away from establishing this robust cause and effect. Dr. Sean Kane 10:31 When you say non authoritative, that means that the parents aren't being as strict or stringent, Speaker 1 10:37 or even that authoritarian style, you know, you know, coming out saying a little because I said, so that's why. And so there's some differences there, again, either being completely permissive or being the flip side of it that extremely overbearing. And so again, there's a little bit of data stating that some of those extremes in discipline style can contribute. But again, far away from establishing that's why kids have, why we have. Dr. Sean Kane 10:59 ADHD got it now moving on to treatment. And as we said at the beginning of the episode, we're really focusing on stimulant medications. And I would say the number one question that I get from students or even from patients about ADHD medications is Okay, so my child is hyperactive, and you're going to give them a medication that stimulates them. So how does that even Speaker 1 11:19 make sense? So it's, again, it's one of those when I was in school, it didn't make a lot of sense to me. And so you kind of look at it. And finally, there's a couple theories for how it works. And the one theory that I really like is the idea that background dopamine is actually low in ADHD. So there's kind of this, the background amount of dopamine that should be, you know, should be present to help somebody focus on what's most relevant in the environment isn't there. And so again, it's first glance. It doesn't make sense, because people see the hyperactivity and tribute this to excess dopamine or no adrenergic activity. But the theory is that because of that low background dopamine, the individual to sustain an act needs a burst, and so then the brain just fires, and the brain fires, that's when you end up with a hyperactivity. So the brain's trying to find something to gravitate towards. So that kind of spontaneously fires this dopamine to try to compensate, and these neurons fire to try to, again, increase attention to focus. And then that's what leads to the hyperactivity, and therefore, as a result, providing more of that background dopamine sustained over a period of time may decrease that burst firing, reducing the impulsivity and other ADHD symptoms. Dr. Sean Kane 12:30 So what you're saying is that it's kind of like too little or too much correct patients, and giving a stimulant can kind of balance them out a little bit and give them a little extra baseline or basal dopamine, right? Speaker 1 12:40 There's, there's kind of, you know, a gentleman, Steve Stahl, who does a lot of good teaching this area, uses the kind of the Goldilocks principle is the not too hot, not too cold. And so it to extend upon that. So it allows that dopaminergic function, allows for better planning and executive acts. But in theory, then there's also concern for paranoia, substance use disorder, psychosis or manic symptoms, if used appropriately again for that that higher end of dopamine. Dr. Sean Kane 13:05 And when people think about dopamine, especially in the lay press, they think dopamine equals the reward system, right? So I would assume that that's where some of that potential for abuse can come in correct and that's Speaker 1 13:16 something definitely we'll get to when we talk about the pros and cons of some of these medications, stimulants, as we've kind of alluded to, have been a mainstay of treatment since the 1950s they function by blocking the reuptake of norepinephrine and dopamine, so allowing them to remain in the synapse longer, and thus increasing levels and within the prefrontal cortex and so again, thus, the more it's available, the less need for that that rapid firing to occur. Dr. Sean Kane 13:40 Now, you mentioned norepinephrine in addition to dopamine, for that reuptake inhibition. Is that a component of the mechanism for benefit? Or is that norepinephrine reuptake inhibition just something that kind of goes along with an unintended consequence? Right? Speaker 1 13:54 So great. So it's one that it does as well. Again, the theory is similarly, little bit counterintuitive. But the idea is here They argue that increasing the amount of norepinephrine around then it starts to hit these presynaptic alpha two receptors, and when it hits those alpha two receptors, it actually then decreases over time, so you need a certain amount of norepinephrine to engage the receptors to block further downstream release of norepinephrine. Again, that Goldilocks approach correct, really, of both these neurotransmitters. And so again, initially it was one that, you know, it kind of comes part and parcel with those medications. But, you know, again, something we'll touch on briefly at the end is we also have shown that a medication that just works on norepinephrine also is effective. And so again, they it can be, as you said, part of just That's how stimulants are. They have both, but on its own, norepinephrine can be affected. Dr. Sean Kane 14:44 And I know we are not going to cover these non stimulants at this time, but whenever I think dopamine and norepinephrine re uptake inhibition, I think Bupropion. Is that something, again, we're not going to get too deep into it. Is that something that is on the table for at least a non stimulant in these patients, Speaker 1 14:59 it's certainly not. Going to be your first line options. Very, very off label use. But there are a few studies that have shown that that may be an option if somebody is unable to tolerate stimulants. And that's going to be a common theme here is that stimulants do have concerns. One of the big ones that's come up is stunted growth. There were some studies that have shown a decreased BMI and about a three kilogram weight reduction over a three year period of time. There was another data that showed a two centimeter, one to two centimeter decrease in stature over three years compared to the average. Dr. Sean Kane 15:29 And we're talking about mostly adolescents here, right? So the, you know, three kilograms, six pounds weight reduction, that that's actually not nothing for an adolescent who maybe doesn't have six pounds to lose, Speaker 1 15:41 right, correct. And the other thing that's been controversial is the idea about catch up, meaning that if, for example, if somebody you know is on the medication during the school year, and you say that, okay, I'm just going to kind of stop the medication over the summer months, and we'll kind of let things run wild. Or the idea that, over time, the body naturally adapts and it increases growth at a later period of time. There's some data showing that that may be possible. The body adapts, and so that even though you see that decrease over three years in the long run of their lifespan, it actually it doesn't occur. There's some data showing that, but it's not guaranteed that not all studies have shown that, Dr. Sean Kane 16:15 of course, we're giving a stimulant that's going to increase norepinephrine, so we're going to see increases in blood pressure, especially if you use this long term. And we can see an insomnia and as we'll talk about with the dosage forms, you know, one counseling point for these stimulants is you have to take them early in the morning so that they leave your body by the time it's time to go to Speaker 1 16:33 bed, correct? That's one of these. That's tricky, because you want it to you want the medication to last and have an effect throughout the whole period of time, and individuals in school and studying and engaging in work, but then you need to drop off at some point. So you kind of have to, you have kind of a thin margin for error. Sometimes someone says, you know, I'm working till 8pm but I want to be in bed by 930 and then you have to figure, okay, how can we work to sustain attention during that time frame and then have it drop out? And that's where we have to be kind of creative with the kinetics Dr. Sean Kane 17:00 of some of course, you know, largely based on the mechanism and side effects, are some patients that are just inappropriate for stimulants. And of course, they would go the non stimulant route. So who are some of those patient groups? Speaker 1 17:09 Yeah, some of the ones. Again, a couple things. You're thinking psychiatric, but then also thinking about some of the adrenergic or autonomic effects. So things like agitation are going to be one of them. Again, by, you know, increasing norepinephrine, dopamine may worsen that so severe agitation, you probably want to be careful about these. Glaucoma is another one. You think about any kind of medication that increases norepinephrine, a lot of our antidepressants that are more noradrenergic, you have to be careful about glaucoma. And so if somebody does have severe glaucoma, want to be careful the pressure. So you probably don't want to use it. Tic disorders are a big one, because one of the standard treatments for tic disorders is medications that block dopamine. Sometimes they'll actually use antipsychotics for tic disorders, Tourette's for example. And so therefore, if a dopamine blocker is needed for that, giving a medication that increases dopamine is not going to help. And so that's a big point in which you want to consider something else for treatment if there's a coexisting tic disorder — and it's not uncommon to have ADHD with comorbid tics. Dr. Sean Kane 18:06 and at least in my neck of the woods, when I look through a package insert for these stimulants, you know, these all have boxed warnings that they can increase your risk of cardiovascular disease. This is mostly going to be in adults versus kids, but at least in the adult population, if you had a heart attack two weeks ago. Maybe it's not a great idea to take a stimulant, right? Yeah. Speaker 1 18:23 Well, they'll say, you know, pre existing structural abnormalities, CAD arrhythmias, yeah, all those things. Probably not going to want to use a stimulant, or the very least, want to be very, very careful. And some of the concerns have been debunked for the most part, especially related to the substance use disorder. They've actually, number of studies have shown that giving stimulants in an individual with ADHD actually decreases substance use and criminal behavior rather than increases. It the idea being that you're not engaging in these self stimulating activities or these impulsive behaviors and so that as you manage the ADHD symptoms, that will actually decrease. So that's one that's actually been well well Dr. Sean Kane 18:59 established now. Another one. You mentioned that you know psychiatric comorbidities can be common schizophrenia, so we give dopamine blockers for schizophrenia. Is that also another population that we should not give stimulus. That's an Speaker 1 19:11 interesting one. And again, because I was always under the impression that, yeah, you give a stimulant to somebody, it can increase paranoia, and therefore we shouldn't give it for schizophrenia. But the difference they have found is the specifics of where the receptors are and the where the dopamine balances are. That in schizophrenia, there's actually a low dopamine in the frontal cortex, high in the limbic system, the amygdala and areas that process fear. And so that number of studies, not all, but have shown that you can give a stimulant to somebody to target the cortical functioning, and that you won't get as much of an increase in the the fear and paranoia that they actually can be either helpful or at the very least, not not a problem that you can give them. And again, because of the specific receptor types that antipsychotics work on, they don't necessarily counter one another. So it's a. Area, I've actually had to go back and say, actually, in some cases, may be appropriate. Dr. Sean Kane 20:03 And that actually kind of opens up a whole new rabbit hole in terms of basic mechanism of action with some of our drugs, it's not as simple as this is the receptor it works on it it gets complex in the sense of, it's the receptor and also the tissue type, right? So it's different areas of the brain that it may concentrate or not concentrate in that adds a whole new layer of complexity, correct, correct. Speaker 1 20:25 And so that's why it's been one. And again, these in schizophrenia, those cognitive symptoms, have been one of the hardest things to treat. And so again, looking and saying, Well, if we have these medications that do work on cognitive thing, you know, can they be used? And so that's, I think it going to continue to be an evolving area for research. Dr. Sean Kane 20:40 So Dr. Schuman, when I think ADHD, I think of stimulants, is it true that these are kind of our first line therapy for patients who are appropriate for it, or is it more like benzodiazepines, where we think benzos and we think anxiety, and that's actually not the first line therapy. Speaker 1 20:53 So again, since the 1950s they have still remained the first line treatment. Overall, continue to have a stronger level of evidence, really, than most of the other medications that have come out, unless a patient has contraindications or adverse effects, some of the ones we mentioned. So those are cases we consider others. But in general, first line is going to be choosing a stimulant medication. And so really, to kind of kick it off, dextroamphetamine is going to be one of the kind of grandfather of them all. So initially, in the 1930s there was a racemic form, so a combination of dextro and Levo amphetamine that was called Benzedrine, that was kind of the first stimulant that came out. And then over time, it kind of got cleaned up. And a lot of them, that's what they weren't about, these active isomers and different forms of it. So they made just Dextroamphetamine. They realized that was the more active form. And so since about the 1970s or so, that's been, again, one of the oldies, and it's available in a sustained, acting and immediate release form of it. One thing to note, though, is one study — and only one — did find that dextroamphetamine may be a little bit more likely to have those decreases in stature, but again, that's only based upon one study; most other analyses haven't confirmed that. Dr. Sean Kane 22:05 So, Dr. Schuman, you mentioned that this product is called Dextroamphetamine. Does it have a common brand name that people may use as well? Speaker 1 22:12 Dexedrine is going to be the more common brand name people associate with that one. Okay? And what else do we have? So the other one we have is kind of that I think a lot of people are very familiar with now, is the mixed amphetamine salts. So others decided, after kind of cleaning up the form of it and making Dextroamphetamine, that it was maybe still worthwhile to have a combination of these salts, but in a different ratio. And so they said, Well, what if we do like a three to one ratio of the dextro and levo isomers? And thus Adderall was born, and so it's available in an immediate‑release formulation (peak effect ~3 hours) and an extended‑release formulation (50% IR/50% ER beads). And that's this is where it's kind of unique, is finding out that you can kind of split them up. It was one of the challenges has been with ADHD treatment, as you, as you mentioned, Dr. Kane, is the idea about having the kinetics work for you. So having a medication that works. You know, some of them, you know, if they peak in three hours and have a duration of six hours, that may not be enough for an individual who goes to school and that goes to classes and or goes to work and goes to classes in the evening, or does a combination, or works 10 hour days. And so it's been a challenge of trying to figure that out, as well as the fact that sometimes tolerance can develop or even dependence. And so there's been an idea about, you know, needing to have a medication act for a longer period of time. And so at the same time, though, they found that just giving it as a single flat line actually caused more tolerance to develop. You actually, you need peaks, but you need a couple of them to really have the medication work well. And so because of that, that's what led to kind of combining immediate and extended release, Dr. Sean Kane 23:53 and that was an Adderall XR that has half of the product and immediate release and half the product and extended right? Speaker 1 23:59 So you get that initial peak to about seven hours in that case. But then you also can get other, a little bit of other peaks as well. And so because of that, it's not a flat it extends it out, but not as a flat line. So you get a longer benefit, but you avoid the tolerance from developing. Dr. Sean Kane 24:14 And just to clarify so you said that this was a three to one ratio of the dextro versus the Levo isomer of it, correct? Was there a rationale to keep that Levo isomer, if the initial product went this dextro route, was there some advantage to having the Levo, Speaker 1 24:29 I think some of it may still have activity. Again, it wasn't quite the big one, but it still had some sort of a little bit of a different activity. And so others have, even, as we'll see later on, have even tweaked a little bit a little bit differently that ratio not three to one, but other forms. Dr. Sean Kane 24:42 So what else do we have besides Adderall and then Dexedrine? Another one Speaker 1 24:46 that I think people are familiar with is from from kind of a consumer or just in the media, is ritalin or methylphenidate. And so this one, again, comes in immediate release form as well as different long acting forms. And so immediate release one was in you needed it to. Be three times a day to maintain that effect. And again, that's tricky to remember. And so as well as you're really wanting to kind of have that sustained effect. So the SR, or slow release form came out that one had a delayed response, so you get peak concentration about five hours after giving it. However, it was ended up being more of a flat one. So as I said, slow release ends up being more of a problem. So that was something that was learned from from Ritalin Sr. Is just delaying it the peak and giving it flatter doesn't actually help. And so it's not really a popular formation because of that tolerance that occurs. And so it's got more tolerance than other forms which have peaks. And so this was where the lesson was learned. You still got to have peaks. So I'm Dr. Sean Kane 25:39 going to guess then if we learned a lesson from Ritalin Sr, there must be another product in the market that fixed that lesson. Speaker 1 25:46 Oh, why? Yes, there are. So the first one of them was the LA form of it, or long acting Ritalin. So that one similar has two types of beads within there. There's an immediate release bead and an extended release bead, and they're in that 5050, ratio. And so you get an immediate effect within one to three hours, and then a delayed effect five to six hours, again, almost like giving two drugs in one and so that allows you to have multiple peaks extended over a period of time, lower pill burden, but you don't get that tolerance from the flat effect. Dr. Sean Kane 26:13 So with this Ritalin LA formulation, are there any kind of important counseling points or things to know Speaker 1 26:19 about it? So this is one that one of our pulmonologists had had come up and found a couple of years ago, and pointed out that there's a really, really significant interaction with alcohol in that the alcohol actually causes the entire drug to be released within the first hour. And so there can be a massive neuropsychiatric and cardiovascular implication of again, instead of getting that delayed effect one to three hour peak, and then a delayed effect was five to six hours getting all of the drug, 100% in one hour from adding alcohol. And it's very specific to that dosage form, yeah. Dr. Sean Kane 26:49 So this, like dose dumping effect, has been seen with other products on the market. Historically, some pain medications are another example of that, where you would literally dissolve your tablet in ethanol or alcohol, and then you could get the entire effect, which typically, this is going to be someone who knows what they're doing and they're trying to abuse it for that purpose. Again, one of the reasons this is a schedule two product is that it does have a realistic abuse and misuse potential, yeah, and Speaker 1 27:15 so again, it's one that it's only a couple times come up. We've tried to make that a big counseling point in our adult population that I see in our clinic that has ADHD, so another one of them. So again, there's many, many different types. And methylphenidate, I think, has probably the most different unique dosage forms about it. And so try to cover only the big ones. But there's also an ER form called Metadate CD, and this one's similar to the LA form. But again, instead of that 50:50, it's a 30:70, where 30% of the beads are immediate, 70% extended. Otherwise it's pretty much another, another dosage form, interesting. Dr. Sean Kane 27:51 And if you think about it, you know, if someone just says, I take methylphenidate, there are so many nuances to that. And even if they say, I take an extended release version of it, there's still even more nuances of Speaker 1 28:01 that, right? So again, for those pharmacy students or pharmacists out there, again, the importance of a very specified, detailed med rec in a hospital setting is to make sure that you're getting the right form of it. If some individuals, in some cases, do take, like the extended release twice a day because they feel the the short acting gets out of there too quickly, or they again, work long hours. And to be very careful, if you bring somebody in and give them the wrong form, or you discharge them on a different form of it and maybe get sub optimal outcomes to realize all these distinctions and make sure you're getting detailed results from the patient or the family members. Dr. Sean Kane 28:34 So certainly there are not more formulations, actually, Speaker 1 28:38 and I even kept off a few. So one that's, I think, really cool to talk about is something called the Oros system, and that's going to be another one that's people know by brand is Concerta. And so this osmotic release system has been used with other medications as this patent technology. And it's really cool where there's about a quarter of the drug is released immediately, and then the rest over the course of a day, so up to about 12 hours. There's this push pan where it as the as it fills up with water, it almost causes this expansion of this kind of non drug piece of it, and that pushes the drug out over time. So this push pouch that kind of, again, made up of organic material, that non drug that just shoots it out the other and there's a little, there's a little laser drilled hole on the other side of it. And so over time, it kind of pushes up, up, and squeezes the drug out. Dr. Sean Kane 29:24 And I'm guessing that the remnants of that tablet are going to end up at the end of the other end of the Speaker 1 29:28 patient, I believe. So yeah, so it's a really interesting one, and again, by doing it over the course of the day, but with a peak still before it avoids tolerance. Some number, not all, studies have shown this one to be superior to other forms, like the Metadate, again, not all of them. Dr. Sean Kane 29:44 And then I am a little bit familiar with the transdermal patch Daytrana, but I would guess that that doesn't have the advantage of this bolus‑basal rate for the stimulant. Speaker 1 29:55 Yeah, that's again, one thing to consider is that, since you'd really get one peak reach slowly over eight to 11. And hours, you may be still get some of that same concern about tolerance developing, as well as the fact actually tolerance, but also the fact that you're getting a delayed release. And so the other thing about it is you may not see the effect until later on in the day. And so again, if an individual takes the patch, realizing that, you know, it may it may not, have those first couple of hours. And so if that's an issue, you may need another dose. For some people. Combine it with a little bit of an oral dose for those first couple of hours. And then there's multi layer beads, extender, release solution, oral disintegrating tablet, chewable tabs. We won't get into all of those, but there's a ton of different forms designed to to have maybe an ideal kinetics and decrease pivot over patients. Dr. Sean Kane 30:41 So that's a lot for methylphenidate. I assume that, given how big this market is, we probably have other stimulants in the market. Speaker 1 30:47 Yeah. So another one is dexmethylphenidate. So realize, again, that there's a pharmacologically active and inactive isomers. And so here that the dextro form isomer was the active one. So later on, the company came out the cleaned up version with just that one, and that's Focalin. So again, just like with Ritalin LA, there's two types of beads here. 50% of them are released immediately. 50% slow release. So you get those kind of those two peaks. Again, I don't see this one used that often. I believe it's a little bit pricier. Most, most individuals are on either methylphenidate or the amphetamine salts, or one that's been kind of a hot one lately in our facility, and as well as, I think across the board, is Vyvanse (lisdexamfetamine). And why has that been a hotter one? So this one's really cool because it's actually a pro drug, and so it requires hepatic conversion for activation to dextroamphetamine. It's kind of in the name, and so because of that, potentially less likely for an individual to try to divert it, you know, one of the things, unfortunately, is because these medications work rapidly, it can be, well, if I need to study or I need some quick focus, I'll snort, snort a tablet, or again, you know, possibly I have a nice, smooth injecting it or finding some other way of getting at it. Well, you can't do that because it still has to go through the liver and still requires that first pass metabolism, so using it for a strength and so because of that, for individuals that we are concerned about diversion or who do have a history of substance use or abuse, we try to utilize that and give this medication. So peak effect is seen in three to five hours. This one has a duration of 14 or so hours, given once daily as well, some of a pill burden standpoint. And there's a little bit of data, just a bit some, a couple studies I believe that have shown superiority of this form comparatively. And so there is, there is definitely a population that does very well on this one. Dr. Sean Kane 32:35 So again, that was lisdexamfetamine, yes. That may have kind of a niche in the market, yes. Speaker 1 32:42 And so overall, what's interesting is that short‑acting agents are cheaper and have a higher pill burden and may lead to tolerance, while long‑acting agents are more expensive but have a lower pill burden and may be less likely to cause tolerance. However, not all studies show clear superiority of long‑acting formulations — individual patient response varies. So even though, in theory, again, I would say long acting is going to be probably the best way to go. In practice, it's not always shown that that makes a difference. Dr. Sean Kane 33:26 So within the stimulant group, you mentioned that Vyvanse is becoming a little bit more popular, a little bit of data supporting that is there kind of a agreement among psychiatrists in terms of for adults or for children or any subgroups that might benefit from one particular stimulant over another. Speaker 1 33:44 So there is some disagreement. One study suggested the Concerta formulation of methylphenidate was inferior to Vyvanse (lisdexamfetamine). Mean, there was one study that showed that there was a really large network meta analysis. They called themselves, quote, the most comprehensive comparative synthesis to date. And what they found is, is that the amphetamine salts were the most efficacious for adults and were therefore preferred. That would be like an Adderall, correct? So something like an Adderall, and for children and adolescents, methylphenidate was preferred. What they said was amphetamines, again, still performed better. They found that methylphenidate was better tolerated in kids. You know, as a general rule, I've said, you know, they're all about as good as another, but I want to point out there's this new network analysis, but the tolerability piece, they felt like in kids was a little bit more of a problem. So because of that, sticking with methylphenidate was recommended. Dr. Sean Kane 34:39 And as we mentioned, we're not going to get too much into the non stimulants, but very globally, what are some of the big differences between these stimulant products that we just talked about and then these non stimulant products that maybe would be good for a future episode? Speaker 1 34:51 One of them, again, is the control status. These stimulant medications are C‑II (schedule II). Non‑stimulant medications we usually think about include guanfacine (Intuniv), clonidine (Catapres/Kapvay), and atomoxetine (Strattera) — these are not scheduled. The big, big, big thing about them, and I tell students, as far as counseling, is that they their onset of action is not hours, but weeks. In particular, two to four weeks with atomoxetine, which purely works by blocking the reuptake of norepinephrine. And so it kind of, it's, you kind of have to think of it analogous to an antidepressant. And then it's gonna take a number of weeks to start working. So if you take that one, because you've got to be examined a couple of days, it is not going to start working. And then guanfacine and clonidine, a little bit faster, maybe one to two weeks, but again, still pale in comparison to the stimulant medications. Dr. Sean Kane 35:46 To kind of wrap things up, you know, we've just barely scratched the surface of the stimulants, giving the audience kind of an idea of different products that are out there. The hole goes much deeper in terms of the other things that are available. I would like to say that as a key point for me, it doesn't appear that the ADHD rates are increasing, but there may be some differences from a diagnostic standpoint and kind of reporting standpoint that may be implicated in the perception that ADHD is an increasing phenomenon. Yeah. Speaker 1 36:14 And then another thing, as I said, is despite the identification of alternate agents over the time period, this isn't a case where we've seen the oldies supplanted by newer ones — stimulants such as methylphenidate and amphetamine salts or even lisdexamfetamine remain first line for most individuals. Tolerability considerations may lead to methylphenidate being preferred in kids, but then the efficacy data overall, possibly based upon some newer reviews, may support amphetamines as first line in adults. That being said, there's a lot of considerations before starting a stimulant. You need to really have the discussion about the potential for growth suppression, tachycardia, elevations in blood pressure. In fact, one of the things that sometimes is done is for the weight piece is, again, kids may lose appetite, and so it's trying to time it around meals — given after a meal (so a child has eaten breakfast) then take the medication so it won't interfere with their appetite for breakfast. Dr. Sean Kane 37:08 And then, really, for those patients that are just not appropriate for stimulants, like tic disorders or those with cardiac disease, mostly in adults, there are a number of other agents on the market that are non stimulants, but as you mentioned, these take a lot longer to kick in. These are not agents that are going to start working in hours, but it's more like an antidepressant SSRI type picture, where it's going to take quite a while for those to kick in. And patients need to be aware of that, right? Speaker 1 37:32 And Dr. Kane, as you're well aware, clonidine and guanfacine are, at their origins, essentially antihypertensive medications. And so if somebody has elevated blood pressure, those may be something worth considering. Whereas atomoxetine, because it increases norepinephrine, would still not be good for increased blood pressure. So we've got some abilities there to even to tease out the non stimulants based upon side effects. Dr. Sean Kane 37:53 I think that wraps up today's episode quite nicely. If you want to see Show Notes and references, we're at HelixTalk.com episode 93 we're also on Twitter at HelixTalk, if you want to send us a message in terms of some episode suggestions or just to say hello, we love those messages. And then finally, we're also on iTunes, and we love the five star reviews in iTunes because it helps drive that podcast higher up in the iTunes rank, so that other pharmacists and other health care providers are more likely to see the show as well. So with that, I'm Dr. Kane, Speaker 1 38:23 I'm Dr. Schuman, and on behalf of Dr. Patel, study hard. Narrator - Dr. Abel 38:28 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 38:39 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.