Video How Do Drugs for ADHD Work? Play Pause Volume Quality 720P 720P 576P Fullscreen Captions Transcript Chapters Slides How Do Drugs for ADHD Work? Overview Jeffrey Newcorn, MD, discusses how ADHD drugs work. Okay we got more we got more than 40 participants so I think we should get started especially um because we've heard from Jeff that his talk is going to be jam packed with exciting stuff so it's a great pleasure to introduce Jeff and unicorn. Uh One of the few hall of Famers in our department, Jeff knew corn is a Hall of Famer for chad which is the Children, Children and adults with attention deficit hyperactivity disorder. And he became a Hall of Famer there because of his accomplishments that we all know about in research treatment and education for A. D. H. D. Um Jeff is a professor in our department is also professor in pediatrics and he's the director of our very successful division of A. D. H. D. And learning disorders at Mount Sinai and he's also the director of pediatric pharmacology for the Mount Sinai health system. Um Jeff received his medical degree is undergraduate medical degree from University of Rochester and and his child adult and child psychiatry training at Thompson's and I think as you all know um he's a world a world leader in A. D. H. D. Clinically research um mentoring uh done many many many critical pivotal clinical trials. He was on the D. S. M. Committee for A. D. H. D. Uh He's an outstanding mentor and educator as receive rewards for that as well and he's really been driving A. D. H. D. Um research and treatment for the course of his career. Uh He also works in aggression and destructive cycle pathologies. Um And you know I guess I'll say it one more time. He's a world leader and truly one of the stars of our department and the Northeast challenge. Uh And it's a great pleasure thank you for agreeing to do this and I'll turn it over to you. Thanks joe very much. Thanks for inviting me. Thanks for those of you who are on for coming and I'm going to share my screen um and gonna go back here. Mhm. See alright we ready we're good. So this type this talk is titled how to Drugs for A. D. H. D. Work. I think it I hope you'll come to see that it's a little more than about the drugs for A. D. H. D. I hope it didn't scare away people we're not interested in drug treatment. Um They're my disclosures. I do have the good fortune to work for a lot of companies. Thinking about making drugs for A. D. H. D. Or those who do just tell you briefly about the plan for this talk. Uh Going to review the phenomenology and neurobiology of A. D. H. D. Just briefly going to examine the array of medications currently available, describe their mechanisms through which they exert their clinical effects. And we're going to consider clinical neurobiological clinical and neurobiological mechanisms related to both core symptoms and associated features and uh I think throughout you'll see that it highlights the differences between The restrictive definition of presented in DSM. five and the broader conceptualization of A. D. H. D. Which is emerging in the literature. So what's A. D. H. D. It's clearly a condition that's popular and very easy to find. Good clip art for. Um You have here um the ah behavioral descriptors for A. D. H. D. And D. S. Um The in the two domains inattention and hyperactivity impulsivity on the two sides of the screen and we like to say that A. D. H. D. Is the tip of the iceberg. And if you look at if you look at the criteria obviously if you can strip them down and if you only take the text box you lose some of the richness of detail. But you'll see that they um mainly describe behaviors that are you know uh um frequent uh frequent also and people that don't have A. D. H. D. Um They're certainly much more oriented to child behaviors than adult behaviors even though A. D. H. D. Exists across the lifespan. And they tend to be high frequency rather than low frequency um Events now inside the iceberg of course are pictures of impairments that are all associated with A. D. H. D. And are all greater in people with A. D. H. D. And although they're not exclusively accounted for by A. D. H. D. By any means. And even in HD samples there are greater in people with A. D. H. D. And co morbidity but a PhD in many cases escalates the risk for those rather unfortunate outcomes. Now that said that 80 HD is highly prevalent. And here we list the prevalence across the lifespan. You can see 8-11% of Children depending on age and gender. It's quite a high figure. And even in adults now we have very good data from multiple studies showing a prevalence rate of about 4.5% And a very low rate of treatment. Now the 11% here was from a study that was about 15 years ago. So that's the national co morbidity replication. But uh that's the kessler study uh indicated here And that number is probably still only around 20 or 25%. I thought I would highlight it for the department because I think it's a big issue across the lifespan and it's not just what's obviously known about kids. A PhD is highly heritable. Uh It's almost as heritable as any condition in psychiatry. You can see the heritability coefficient here as roughly what it is for schizophrenia and bipolar disorder, it's somewhat lower than it is an autism. Although I understand that the heritability of autism is dropping a bit uh as you've embraced the the spectrum broader spectrum. Now there have been a lot of candidate genes looked at mainly within the mano mean system and specifically in the catacombs immune system because of what we know about the neurobiology of attention inhibitory control and the way that stimulants work and we're going to talk about that. Um But these have very small and they're replicated but they have very very small effect sizes and trivial. Uh geneticists would tell us Now. Recently last year we had the first successful Gwa study of over 20,000 cases Which identified 12 independent Jean Los I associated with the disorder. None really of the candidates. And one of the interesting things there are many interesting things about that study. But one of the interesting things is it shows that the genetics of inattention and A. D. H. D. Is quite similar to the genetics of inattention and the population only reinforcing the point that A. D. H. D. Is a disorder but it really exists on a continuum. It's been drawing this Slide four million with me over the last 20 plus years. Um I should really get rid of the build anyway. It mainly shows um an early uh an evolving a picture of the neurobiology of A. D. H. D. Certainly with a primacy on the front of straddle networks and regulation through cerebellum and the catacomb energetic inputs. Um We updated for a presentation on a drug development showing the basically the the receptors and transporters involved in the various brain regions and the modulators all of which are potential drug targets. But as complex as this um figure may seem to some of you it's really very simplistic in terms of evolving understanding of the biology of A. D. H. D. Now um That the last slide really showed you the primacy of the front of straddle executive function uh circuit. But over the last 15 or 20 years we have had um you know the expansion of the model of A. D. H. D. And this dual pathway model I think is really interesting and important. Postulated by Edmundson yoga bark and colleagues. Javier castellanos was also uh important in advancing this model. As you can see the slide shows you um you know on the top the neurobiological basis in circuitry the psychological processes and the behavioral expressions. And so uh you know on the executive circuits side we see as expected inhibitory control deficits and attention and executive dysfunction. And on the other side and the reward side we see a delay aversion, meaning it's really hard to wait. Uh And delay reward gradient being shorter. That means that you need more immediate reinforcement here. Think the marshmallow test right? Uh So you've got to have and and also think about the consequences for behavioral therapy. You've got to have immediate reinforcement. You can't prolong it, you can't wait and you can see you can through both sides how you would get to the behavioral manifestations of A. D. H. D. Not considering all the options through both the reward and the executive side will lead you to inhibitory deficits. It'll lead you to inattention will lead to a lot of other issues. And as you can see in the middle of the slide will also might lead you to emotional dis regulation and we'll talk about that in just a moment now rubio and rubia advanced this model suggesting the neuro violent neurobiological underpinnings of the dual pathway model showing the brain regions and networks that are involved in executive control on the left side of the slide. Uh And you know the ones that we know and talk about so often in A. D. H. D. Inferior frontal cortex. D. L. P. F. C. Interior singular. Um um And and also the striatum and the cerebellum. But over here on the right side of the slide you see a lot of limbic structures related to affect the modulation and control which we have not typically thought of as implicated in A. D. H. D. So what about emotional dis regulation and A. D. H. D. Well it turns out that it's quite high and it's not solely accounted for by co morbidity. And we know that about 30 to 40% of Children and adolescents have significant impairments and emotional dis regulation which might look like rage outbursts, irritability over reactivity poor frustration tolerance susceptibility to anger. So these go well beyond uh what we would call of course symptom Atala ji of A. D. H. D. Into emotional control. And it's interesting because we've thought so much about cognitive control and inhibitory control behavioral control. Right? But we haven't really thought about emotional control in A. D. H. D. Or at least in terms of the cardinal description of the disorder. And I might have told you earlier. But didn't that that the definition we have of A. D. H. D. Has really been with us more or less as is with minor modifications Since the SM. three in 1980. And you can see at the bottom of the slide the number of publications that show you prevalence of emotional dis regulation and adults with A. D. H. D. It's quite high. And you see also that um the behaviors linked very much to mood regulation as well. It's very interesting that in the original conceptualization of adult A. D. H. D. Advanced by paul Wender. He really emphasized the um the poor frustration tolerance and the short fuse and the emotional reactivity. And a lot of people were critical of his original conceptualization. Thinking that he really was getting A. D. H. D. Um confused with depression. Um And that's an interesting um and provocative area for both clinical work and research. Now the conceptualization of emotional dis control also gets I think it's really nicely illustrated in this figure that was um included in the paper that I co authored with Steve Sharon and several other colleagues and it basically talks about um um basically a bottom up and top down model of emotional control. So thinking about uh so emotion generation. Right? So ah so which you might consider emotional impulsivity having too much emotional ah mm signal and uh you know strong emotions. And then thinking about the top down regulation of that um which would be impaired emotion regulation or inhibitory control of emotion and so called deficient um emotional self regulation. DSR as it's been studied by Barkley and and Peterman and and colleagues. Um So I think and we'll talk about this a little bit more. And there you have those names. Now I mentioned the importance of little of motivation, reward, reward circuit and motivation is linked to reward. And this figure was taken from a paper that we did with Nora Volkov when we were doing Pet Radio Liggins studies of adult A. D. H. D. And it shows that the ratings of inattention are correlated with ratings of motivation. And this is on the multidimensional personality questionnaire. And this was true in individuals with A. D. H. D. And it wasn't really true in the healthy controls. And it's it's a really important clinical point as well as a neurobiological point because it speaks to something that everybody knows about which is that everybody with can pay attention and also that everybody without a Dhd cannot pay attention and it really depends to what you're trying to pay attention and um and for how long and uh and uh and you'll see that the important implications of this both in research and in clinical practice as the talk develops. Now another important construct to introduce here Is the role of the default mode network that has gotten a lot of attention over the last 15 to 20 years and basically is um what you measure when you do resting state FmRI. And when we talk about attention and areas that are involved in attention and so called executive function circuit. We're really talking about the brain regions that activate when you're doing a structured tasks. And um what um what we originally called the default mode network is what your brain was doing when it was not doing anything. Although we know the brain never doesn't do anything. Always doing something but in the case of not doing anything it's not doing a structured task. So it's I think nicely labeled here as task positive and task negative And you know although you don't want your default mode network to be really active when you're trying to do math problems. It's very nice for reverie and it's nice for fantasy and it's nice for also for consolidation and it may be important in terms of understanding of creative process. So task negative brain regions are very important but they're not they're not important to getting structured task done and we want to suppress them when we do that. And so this slide kind of summarizes the current view of A. D. H. D. Multiple cognitive and emotional processes and interacting brain networks. And so here you have the cortical uh brain regions dorsal and ventral attention network and here you have the sub cortical brain regions with the, he endorsed the dorsal anterior cingulate and ventral cingulate cortex. And and here you have a quad eight and we'll talk about the amygdala and a bit and cerebellum. Here you have the cata cola mean networks and their projections. Here you have the executive control network um And here you have the reward network and then you have alerting arousal learning. And then here you have default mode. So all of these all of these brain processes are implicated in A. D. H. D. And so to briefly summarize this ah D. S. M. Defines a rather narrow picture of A. D. H. D. With a primacy on inattention even even much more so than executive function which we think of as synonymous with an attention but it's a it's a more sophisticated and complex construct and hyperactive impulsive symptoms but presented in a rather narrowly defined way consistent with the front Australian model of the disorder. Recent models and certainly a lot of research and A. D. H. D. Has highlighted the importance of several other symptomatic and functional domains with an expanded view of executive disfunction, mood, dis regulation the important roles of motivation and salience. And certainly studies of a dhd path of physiology are consistent with this expanded conceptualization of A. D. H. D. Which has important implications for diagnosis and treatment. All right so we take a deep breath and we now shift into talking about um medications for A. D. H. D. And how they bring about clinical improvement. So this is a slide that I've been making and remaking and um and updating over the last at least 10 years. It basically includes every drug that we have for A. D. H. D. Including the ones who are studying. It includes those who are approved, those who are not approved and it does list them in brand name I should say because you would have no idea what we were talking about with these multiple stimulant formulations except by their brand name. But there is a key using using the generic names. Normally you do it the other way around but basically at the end of the day what do we have? We have two classes of stimulants. We have methylphenidate and we have amphetamine and we haven't been a lot of different formulations that basically relates to um duration of activity and and how you get it in. So you know we have we have pills, we have capsules, we have beads, we have liquids, we have chewable, we have orally disintegrating tablet. We have a patch where's the patch? There it is. Um And uh and then we have two approved non stimulant classes. We have adam oxytocin or Strattera and we have the long acting alpha two agonists intuitive and cafe or long acting Guangfa scene and long acting cloNIDine and then we have. Mhm. Drugs that are not approved Most of these don't have extensive study. The short acting Alpha two agonists do. Um They were the base the basis for the development programs for the longer acting outfit. Two agonists. The tricyclics have a reasonable amount of research as well and um and Wellbutrin has multi site studies in both Children and adults but doesn't have a label and isn't isn't likely to go after one. So what does stimulant treatment do it improves course? And we're gonna talk first about stimulants. Um It improves core symptoms of A. D. H. D. With a very high effect size about as robust as anything we have in psychiatry. But it also provides improvement for a lot of associated features including behavioral noncompliance, impulsive aggression, social interactions, social awareness, academic efficiency meaning getting through stuff faster. Academic accuracy, not making careless mistakes, family dynamics, improved peer interactions and and self esteem. So how do they work? Um basically this cartoon gives you a nice illustration um So pre synaptic post synaptic neuron synapse um stimulants block pre synaptic transporters that suck neurotransmitter back up into the pre synaptic neuron adam oxytocin or Strattera does that as well. Uh stimulants do it for both norepinephrine and dopamine. Although people talk a lot more about dopamine and norepinephrine and adam mox mox team does it exclusively for norepinephrine and not dopamine um has a little bit of activity at the serotonin transporter as well as you can see um adama amphetamines also blocked re uptake into these interest synaptic vesicles. Um And so you have more free floating uh neurotransmitter in the presence of amphetamine which diffuses out. So amphetamine increases neurotransmitter release as well as blocking of re uptake. And I see I have a typo there as many times as I've looked at this. Um And so you know, it's basically a schematic and how do we know this? We know this through some very sophisticated radio Ligon studies. The slide was provided by Nora Volkov and it shows basically the um um how um stimulants like methylphenidate find to the recent haptic dopamine transporter. Basically what you do is you give radioactive ligand that binds to this transporter. And uh first you give it without drugs and you see the ligand, that's what you're seeing here in the striatum and then you give drug and you block re uptake and and and you see here you see much less of the ligand. It displaces the lignin from here are you also can use Liggins for post synaptic activity here. It's regular pride. And uh and so you can you can quantify all of this. And in fact. Um this slide shows you the effect of stimulants on norepinephrine and dopamine transporters. Dopamine on the left norepinephrine on the right and it shows you that you get a very nice um um dat occupancy. Um those relationship And that Aston took about 50-70% de 80 occupancy and it works and it's right within the clinical range. So about a half a milligram per kilogram per dose about about what you want to give for methylphenidate. And you see this is dose dependent. So this is I think 0 20 and 40 mg. You can you can see you get you get a nice dose dependent. Um Finding initially these studies were done with I've methylphenidate but they were also done with laurel methylphenidate. And and and it works just fine. Now you can you can use dat occupancy to look at the time course of activity of drugs like for uh for A. D. H. D. Particularly methylphenidate. You could do it for amphetamine too. You have more trouble with the amphetamine but um so here is a study done by my friend and colleague tom Spencer uh and uh in mass general. And here you have immediate release methylphenidate and here you have osmotic release so called so called Oros methylphenidate which has a brand name of concern to and you can see that this is the peak a curve. And this is the binding curve. And you can see that how the P. K. Curve is more or less more or less informed by the by the binding and shows how these drugs are are different and behave differently. Now a lot of work has been done with with FmR. I also structural M. R. I. But I'm not going to really cover structural M. R. I. Today it's not really good for showing drug effects. Um kati rubia has been one of the leaders in this and um she did a meta analysis of of of M. R. I. Studies functional M. R. I. Studies showing mainly the uh findings both both for increased activation in right inferior frontal cortex and decreased activation in anterior cingulate both of which were. And those findings were uh huh. For A. D. H. D. Versus non A. D. H. D. And then drugs versus versus placebo. So these are the drug effects and um they're reasonably consistent across studies again highlighting the um the attentional control and inhibitory control um improvement that you see with these drugs but we know that stimulants do more than that. How do we know it? And we know that don't mean transporters are not only in the striatum. So this was one of the earlier studies we did also in collaboration with Brookhaven group and Nora And um and basically what we found was low dopamine A transporter activity and d. two d. 3 binding. And this is the D two d. 3. And you see it here mm hmm. Not only in in the striatum but you see it extending out here into the into the limbic system and this is you know it's graphed out on the bottom so controls and A. D. H. D. Lower density and you can see you can see all the brain regions and significance is marked here robust in quarters but quite prominent in the amygdala here and hippocampus and it turns out that increased amygdala activity and amygdala prefrontal connectivity is not only characteristic uh is importantly affected by medication. So Jonathan Posner in a you know a small and Fmri study but but but very interesting showed higher activation of the amygdala and greater amygdala prefrontal connectivity and youth relative to controls when subjects were exposed to emotionally evocative stimulant. And this difference was greatly reduced by administration of methylphenidate. And so going back to our model of emotional dis regulation and A. D. H. D. What does this mean? Higher activation in the amygdala would be greater emotionality and um a greater amygdala prefrontal connectivity might or might not be a good thing. It depends on how you're looking at the connectivity. Is it connect if it's connecting you know the direction if it's connecting prefrontal to Magdala, you're talking about inhibitory control but uh what you typically focus on here is transmission of the signal from the amygdala amygdala to frontal cortex. And so the greater connectivity is not necessarily an advantage both improved by drug treatment now not everything that goes on in the limbic system is related to emotion. There's also such a thing as the cognitive cognitive control of the motion and that that was shown in this study that kurt Schultz lead from our group and what is shown here is that this was a study with 25 adults with A. D. H. D. Who was scanned twice With Fmri. They were performing an emotional go no go task after 3-4 weeks of treatment Would list X. Amphetamine or vivants and also 3 3 weeks off medication which was a combination of placebo and um um um and wash out or work uh um wash out before the before the trial. And what you see is that um um L. D. X. Vince was associated with increased right amygdala activation and reduced interactions with orbital aspect of the left inferior frontal in response to sad faces. Sad faces is where the action always is in this particular version of the task. But the interesting thing here you'll see on the bottom of the bottom right of the slide is that the association here the relative gain in right amygdala activation in response to sad faces with drugs was correlated with a reduction in symptoms of Adhd. So here you have a brief emotional control scales. So this was not related to emotional control. It was related to A. D. H. D. Symptoms and attention which um we uh took to mean that um it wasn't what what what what the drug was doing here was helping you detect the sad face and so reading the emotion, the cognition of the motion. Now I mentioned the default mode network before. And uh this was studied by brad Peterson in Colombia showing the effect of methylphenidate in increasing suppression of the default mode network while doing FMR I task F. M. R. I. So you do suppress and you want to suppress it more. And so that would be a positive effect of the drug. And you see it here in the red box on the slide and the areas are identified below. And and the implication of this is that the brain can work more efficiently when you suppress default mode activity. You don't have to drive it as as much. And this particular slide from a study that Nor Volkov did in Brookhaven, we we we we weren't part of this slide. This study um looked at glucose utilization and adults who are doing um uh numerical calculation and they had greater glucose utilization on placebo than methylphenidate, meaning that the brain was functioning more efficiently on methylphenidate. And um and it didn't have to work as well. And we'll come back to this because it becomes important to our model. I'd like to walk you through this slide in great detail but I don't think I really have time but it shows a really important interaction between default mode network modulation motivation reward and inhibitory control. This was an FmR I study that looked at um a motivational incentive paired with a go no go task with and without drug and controls, basically what it showed is that, you know in the high incentive condition off mental methylphenidate the brain looks pretty much like it does in the low incentive condition on methylphenidate meaning that um that you probably don't need as much methylphenidate in a high incentive condition as a low incentive condition. Actually explained this to one of my patients yesterday who couldn't figure it out why he was able to take a lower dose on a project that he really really was into. And so this I think is really interesting And you can see in the high incentive drug condition you basically are starting to replicate what you see in the in the controls which is really I think fascinating. Um Finally I just want to say that a lot of recent studies in uh in the area have begun to look at um a larger set of brain connections in relationship to A. D. H. D. And drug treatment of A. D. H. D. And this one highlights the fact that um basically what what methylphenidate is doing what stimulants are doing is improving broad broad network connections across multiple networks and so focusing in on one or the other is useful. But but really the broader view may well be more important. You can see the ones that uh that were implicated that was strengthened by by uh by drug importantly the attention network and executive function network and uh etcetera salient network. And so what do stimulants do they bind to dopamine and norepinephrine transporters. They increase synaptic dopamine and norepinephrine. They modulate activity in frontal straddle network. They suppress default mode activity, quieting noise enhancing signal, allowing the brain to work more efficiently. They alter limbic prefrontal connectivity So they help modulate emotional control. They enhance activity and reward and salience networks. They increase motivation and sensitivity to reward. They make tasks seem more interesting that are boring that people don't want to do and they strengthen network connectivity more broadly. All right we're gonna move on to non stimulants. I'm gonna have to pick up the pace a little bit stimulants are extremely effective but there's poor response to cholera bility in some patients sub optimal response in many patients. Um time action effects are problematic with stimulants. Um stimulants can be relatively labeled contra indications for some co morbid conditions. Some patients won't take them. Some doctors won't prescribe them and there's definitely risk for diversion or abuse of the drugs were scheduled to drugs. There's been a lot of interest in um developing non stimulant alternatives for A. D. H. D. Now adam oxytocin I told you selectively binds and norepinephrine transporters not so robust here and the dose effects are not as robust really. The norepinephrine transport ligand is not as um as effective as the dopamine transport ligand. And and so that's one of the reasons that we know a lot more about the role of dopamine in A. D. H. D. Than we do about norepinephrine. I mentioned that there is a little bit of activity. The serotonin transporter as well but it's quite low. And one of the interesting things is that you would expect. And um oxytocin to increase dopamine levels and norepinephrine level. I always mess up this slide. You'd expect it to increase norepinephrine levels in the prefrontal cortex. You'd expect it to increase norepinephrine levels in the brain, diffuse flee. But you wouldn't necessarily expect an increase in dopamine in the prefrontal cortex. But look here this is micro essay study in rats in which um oxytocin and methylphenidate are injected and there are transmitter levels are measured and you can see that you get the same picture for adam oxytocin as you do with methylphenidate. And the reason you do is that norepinephrine transporters are plentiful in the prefrontal cortex. And don't mean transporters are relatively absent. And so uh dopamine re uptake is achieved via norepinephrine transporters. And so it is absolutely correct to say that adam oxygen has direct effects on dopamine and prefrontal cortex although it does not have effects on dopamine and striatum. And here you see that um this this effect on dopamine is only seen in the prefrontal cortex. You don't see it in the striatum nucleus accumbens. So this is an early study done in healthy adults by sam chamberlain with Trevor Robbins in in uh London showing that adam oxytocin increased right inferior frontal activity very similar to what you saw with with methylphenidate um and this is go this is stop signal task. And so you see the activity is associated with successful inhibition and that's really where it's most important. And you can see it's selective, too successful and ambition. Now adam Augustine is not as effective as methylphenidate on average, it's a really big comparative study funded by eli lilly. We were one of the sites in it and um I was one of the lead investigators in it and um Which this is over 500 kids Um treated with Adam oxytocin methylphenidate and placebo in a 2-1 randomization and the outcome measure here is percent responders rather than symptom change. But you can see it here for all patients. Um um and you can see both drugs do a lot better than placebo. Um but methylphenidate does better than adam oxytocin and um and that is mainly carried by the ones that are previously treated. You see this, you see the same relationship but a much smaller effect that isn't significant in the group that stimulate naive this. This figure doesn't appear anywhere except my slide decks. It wasn't taken from the paper I made it actually after several years ago to describe a few lines of text in the paper to show you that there is really a relative bimodal response at a market animosity and pre marketing clinical trials. This is this is non responsive less. I call it non responses change in symptoms of 25% or less. And considering the placebo is getting you 15-20 years plus. I call that non response. He said you basically you see quite good response and basically relatively poor response with not a lot of people in the middle. So this is exactly the kind of drug that screams out for the need for personalized treatment approach because you want to identify these people and not these people. And by the way this is a pretty high level of non response. So we did the study that we called macro which is an acronym that stands for methylphenidate adam, Augustine crossover. It is a very large and torturous study to do. It was done here and in Chicago with my good friend and collaborator Marc stein and with a lot of good friends and collaborators here but notably Kurt Schultz doing the imaging piece of this um and um this is just a schematic of the study we treat it was no placebo in this study we randomized the order. We had a two week washout in between but people knew they were on washouts, we'll see about washout so they wouldn't get out of the habit of taking drugs um and um and there you have it and then afterwards we're able to get um we were able to get um funded to do um um um first a pilot and subsequently A larger R12 to look at the impact of drugs on mari uh These are the clinical findings that actually replicate the lily findings. I don't want to belabor this. Um We have more expectancy in the first block. So the Cohen's D. Is lower and doesn't quite reach significance. We powered at about .2. You can see uh more robustly here. You do have a little bit of carryover but not not too much and it's not it doesn't differ by drugs so uh that looks really quite good. Um And it basically shows what we know. What about the imaging study. Okay so these are 18 subjects uh pre and post treatment with methylphenidate and 18 on Adam Oxytocin task M. R. I. Um And this is basically a um and what you see um it's it's uh I don't know go task. And what you see is um common effects here and divergent or unique effects here on the right side of the slide. So common reduction and activation in motor cortex and divergent effects in inferior frontal A. Cc. And BCC posterior cingulate. And so what does this mean? It was very very consistent with our model of the atom oxytocin driving cortical activity and um and the attention signal and methylphenidate increasing efficiency and how the brain works. Um We think that um posterior singular default mode activity here is really key. Um And you know why why do why do these other areas go down? They don't have to work as hard uh here. Why does posteriors singular go up here with adam oxytocin. We're not sure. Some people have found increased atom oxygen activity in default mode but but we think it can we think this is driving the response. And were involved in some analyses now with two that greatly expand the sample to allow that will allow us to test the model. I just tell you that um Susan gao in Taiwan did a similar study different tasks and basically found same regions having divergent activity although in a different direction, possibly task related, possibly other things, possibly the analytic platform. But so again, some convergence of findings here. We wanted to then look at the specific predictors of this to look at whether the FmRI profile could predict differential response to methylphenidate and animosity. And we had the hypothesis that differences in straddle activation off drug might predict differential response. So this is the second analysis from the same study. 36 youth who completed treatment with both medications for 6 to 8 weeks. Obviously a lot of them were in the first publication but not it's probably about three quarters because in the first one you just had to do the first block and here you have to do both treatment blocks. Um and we examined both main effects which would be a profile associated with response for each drug and interactions which would be associated with differential response here are the main effects. You see a main effect for adam oxytocin and motor cortex. We had a finding for adam oxygen in motor cortex previously and you're basically what we're showing is that um motor cortex activity increases as you're getting improvement with with animosity and you see the art here is pretty good. I mean it doesn't explain the whole phenomenon. It's about a third of the variants accounted for. This is the really most exciting finding from the study which is the differential response finding. And this finding shows that increased baseline caudate activation was predictor of superior response to methylphenidate over adam oxytocin here you see uh the brain map and here you see the the heatmap heatmap basically just is a three dimensional map. So the Y axis shows you change score improvement for adam oxytocin. Um And the X axis shows u improvement for methylphenidate and colo Urs show you brain activation in this region. And what you see here is, you know, you know, the highest brain activation is over here. And um and what do you see you see the people that had that had really um very very robust responses to methylphenidate and very little response to adam Och city. No ah 75-100%. You know, we'd say 50% is a robust responder, maybe even a you know called a perimeter. And here you have Um it just just about, you know, it pushes up a little bit through but you're 25% or lower, you know, almost all of it for animosity. So adam oxytocin increases synaptic dopamine in the prefrontal cortex in north china from def usefully it drives prefrontal activity which we think increases attention and responsiveness to signal. It enhances inhibitory control via activity, inferior frontal gyrus. It doesn't really have a direct effect in the caudate or ventral striatum which at least in our hands, which suggests that it should have minimal effects on motivation and reward. Um There are uncertain effects on default mode network in our hands. We don't think it does. Others think it may so I'd say maybe task dependent. Um and there are notable similarities and differences from methylphenidate. I'll trade it, take five minutes to finish up And talk to you just quickly a bit about the Alpha two agonists. This beautiful cartoon was drawn from taken from a paper from Amy Ornstein's lab in New Haven And it shows you the cellular effects of of the Alpha two agonists that she has. She in her lab have mapped out they worked extensively with want to sing. And what they show you is that Qantas seen plugs up this ion channel uh that um when it's open prevents a signal from going forward and when it's closed allows post synaptic transmission of the signal and you can see that this um this post synaptic receptor modifies um neuro transmission of other neurotransmitters here, it's an excitatory glutamate neuron. And uh and um I mentioned about the post synaptic effects because um um the alpha two agonists also have pre synaptic effects. And a lot of people thought that um that that's how they carried their effect. But it wasn't until this became known that we can see that mostly effect of the drug is posting of the other drugs are post synaptic. This is from a study that Suzanne Clarkin did with our group uh Kirk mentored looking at I think I'm being told I have to wrap up. But let me see oh no I'm being asked the question. I'm going to put that on pause. How do I make that go away? Okay. Um And this is healthy adults, basically young adults a lot of queens, college students who were scanned twice once on placebo and once after one mg of immediate release Qantas scene. And they did a cute alerting task. It was basically a target detection and they had to respond. And it was basically measured reaction time. And um what they found is that with the Q. They and and you have increase in let's say I can show it to you here I want to sing relative to placebo a smidgen here but most of finding here is in D. L. P. F. C. It's exactly what this drug was drawn up to work. It's exactly what they found in animal models and it should suggest a drug that works really well for um working memory and cognitive control and executive control. But it's interesting that what we have learned. Why is this not advancing? How do I why is my thing stuck? Okay. Um is it Guangfa scene is not as good for attention and cognitive control as a stimulus and maybe not. Uh And and and at least in the studies of guan facing long acting there's a little bit of an effect size uh superiority for hyperactive impulsive symptoms than inattention. And basically people give this drug more for behavioral control than cognitive control and A. D. H. D. And you can use it for adults too for restlessness and things that they may not come to treatment for. That may well be very important. The question is why is this And a little more work from kurt in our group on the effects of Guangfa seen using the face go no go task again. Looking at sad the sad face here showing that Qantas in altered the connectivity between amygdala and inferior frontal gyrus in association with improvement and negative bias in response to sad faces. So we think that wants a scene actually improves emotional control um and emotional control may as we know oppositional symptoms which I showed you in the slide before our very heavily influenced by emotional control as well as cognitive control. Um And so we think that maybe the reason that this drug has a very good effect on emotional control. We also did a drug placebo study looking at Qantas scene and um it's a pilot basically we use CG II here rather than symptom change because we had too high of a symptom change on placebo. But what you see is um basically that Guan facie had an effect that mid cingulate cortex um reduced activation for Qantas and compared to placebo there and uh into left posterior pcc. But and it's interesting it's very similar to a finding from George bush early on with methylphenidate. So I would count this as a mainly a common effect with methylphenidate. So to summarize Guangfa seen by binds to post synaptic ion channels and facilitate signal transmission. It increases activation in the prefrontal cortex. It enhances alerting mechanisms. It has effects on attention and executive function but they are less robust in humans than then. The effects are for hyperactive and impulsive symptoms. It decreases limbic activity and limbic prefrontal connectivity and potentially modulates modulates emotional reactivity and emotional dis regulation in A. D. H. D. And this decrease in activation and mood Singulair may represent a common mechanism with stimulants. I'm just gonna move to the take home message is quickly just to say that A. D. H. D. Is a multifaceted neurodevelopmental disorder that has a strong biological basis and the expanding conceptualization of the disorder highlights several important clinical domains of interest beyond what we tell you and GSM the effective treatments for added impact multiple brain regions um and um including attention and executive control, default mode activity, reward and motivation, salience and emotion regulation. The effective medications have both common and unique effects, unique effects provide a rationale for combination pharma co therapy and a neurobiological basis of differential response. Are there biomarkers of differential response? Well we're very intrigued by our findings and those of others but we would have to say not yet. These are interesting preliminary data certainly wouldn't. I want to recommend that people get mris and the clinical observations regarding a broader a dhd phenotype line up really well with finding some neuroimaging studies. So the current definition of A. D. H. D. In my opinion which maps most closely onto this restrictive front of straddle model isn't fully adequate and I'm gonna stop there, joe is going to give me the hook anyway if I don't stop. Thank you for a great talk. We're at the top of the hour and I already said that some people are moving to the next talk but maybe if you want to there's a couple of questions in the hot box. Um I guess I'm reading from the bottom up here but Nigel Kennedy thank you for the great talk. Uh but wondering whether practitioners should lower the threshold for starting a stimulant because he's concerned that it's undertreated. It's vastly under under treated. Um Of course everybody who gives a talk advocates that everybody should be very interested in the thing that they do and I'm certainly not any different. But here's why even if you're not like an A. D. H. D. Maven you should really think a lot about identifying and treating A. D. H. D. In adults. People that A. D. H. D. Is commonly represented in people with depression. And if you think about it, the low motivational state in A. D. H. D. May share clinical and neurobiological commonalities with the anti Donia of depression. And we know that um A. D. H. D. Is overrepresented in treatment resistant depression and uh that um treating A Dhd can actually be very helpful for that population I guess lining up with an old finding that amphetamine was often used as an early treatment of depression in the elderly. Let's go to the 2nd 1. What factors would I consider? Oh that's a long discussion uh about treating A. D. H. D. And bipolar disorder stabilize the bipolar disorder first. And then definitely look at the A. D. H. D. Because a lot of people with bipolar disorder, the vast majority of adolescents with bipolar disorder have A. D. H. D. Do the medications make long term neurobiological changes that may resolve some of the symptoms. Well one would hope so but uh we know that typically when we withdraw medications for A. D. H. D. People don't maintain their benefit. Now they could make long term changes that um that uh don't aren't maintained when you withdraw the drug because there can be other changes that serve to maintain homeostasis by the way. Some of the neurobiological changes that occur don't really take that long to occur. Some of the neural anatomical changes that occur at the receptor level probably occur relatively quickly. So and you get you get up regulation of D. A. T. And down regulation of D. Two and D. Three receptors. So you may actually have people get a little worse when you take them off stimulants even after a moderately short trial. There is some interest in white matter and changes in white matter uh with stimulant treatment over time we'd love to be able to show that this is the case. Most often. People who have looked at changes in the brain with stimulant treatment have wanted to focus on whether stimulants damage the brain. I think that's really an unfortunate way of looking at the problem. Of course. Both questions have relevance. Yeah I got those three. Are there more? Well why don't you take the last one? Nigel had a second one. Oh practice question. What are your thoughts on neuropsychological testing for diagnosis? Should this be done routinely in every patient? So I think the simple answer to that is no and I hope not to get into too much trouble with my neuropsychologist colleagues who I love admire and value very much now. Russell Barkley says. Emphatically that neuropsychological testing is not needed for that I would say is should be moderated. Now. One of the reasons it's assuming I'm right. It would be good that neuropsychological testing is not needed to make a diagnosis of adhd. Is that neuropsychological testing is expensive. It's not easy to get what is neurosis. It definitely can tell you about A. D. H. D. But there is no test that actually is required to tell you whether you have A. D. H. D. What neuropsychological testing will do is present a robust profile of relative strengths and weaknesses and functioning. And it is required for getting accommodations in the educational setting and sometimes in the occupational settings. Okay I think we should probably stop there. Um Thank you very much for a great talk. A lot of very excited interesting participants um and thanks for doing this and uh yeah thanks for inviting me and I'm happy to continue the dialogue with anyone who's interested. Of course thank you all for joining. There'll be another we'll have another one of these virtual seminars in two weeks. Thanks Jeff. Bye bye. Published November 30, 2021 Created by Featured Faculty Jeffrey Newcorn, MD Director of the Center of Excellence in ADHD and Related DisordersMount Sinai Health System View full profile
