Chapters Transcript Guidelines for the Diagnosis and Treatment of Adult ADHD Course: Update on Attention Deficit Hyperactivity Disorder Through the Lifespan So we're gonna be talking about an update on the diagnosis and treatment of adult ADHD. We're not gonna be able to talk specifically about the guidelines as promised originally because the guidelines aren't out yet, but we'll talk a little bit about um what the guidelines might look like. And this talk actually will frame in some ways, some of the issues about what the guidelines are going to look like, but can't talk about the guidelines yet because they are embargoed. OK. So, I have received a grant research support from Atsuka, Korum and Collegium for doing research on adult ADHD. Those funds go to NYU. I have consulted over the last 3 years with Shire Takeda Atsuka, um, Bracket Cignet Neurocentria and developed the therapeutic use exemption guidelines for the NFL and MLB. And I've received royalty payments as inventor from NYU for the license of ADHD scales and training materials. In this talk, we'll talk about some off-label treatments of executive function deficits and emotional discontrol, um, and also talk about off-label use of prison EFP neurofeedback for ADHD. So, uh, rather ambitious agenda. We're gonna move pretty quickly through some of the background work which you may have heard me talk about before. I'm gonna focus somewhat on the diagnostic criteria for adults, um, the associated symptoms, talk about our standard pharmacotherapy and more about some of the newer data that's available from some of the newer therapies. So I like to put this up as the timeline of what we've called ADHD over the course of time. Um, it's important to understand we've been in, in the literature looking at case descriptions of ADHD going back at least to 1902. These are, uh, descriptions of kids with ADHD. It was a monograph written called Fidgety Phil. Those kids would look like kids with hyperactivity, significant hyperactivity, impulsivity. Um, we would diagnose them with ADHD currently. The first use of medications actually goes back to 1937. George Bradley uh gave Benzedrine, um, amphetamine to kids who were getting neuroencephalgrams. There was, you have to introduce air to try to get a contrast media for, so the post-hap headache was significant. They were looking for medicines to try to treat it. The kids who were hyperactive before the pneumoencephalogram who got the benzedrine were not hyperactive afterwards. And therefore the first use of medicines to treat ADHD-like symptoms. Noting that um we really um did not study adults with ADHD was conceptualized purely as a childhood disorder until the mid-1970s when Paul Wonder at the University of Utah saw adults presenting who'd been diagnosed with ADHD um in childhood and had ADHD-like symptoms in adulthood came to him and he gave them psychostimulants and lo and behold, they got better. DSM 3R in 1980, we could make a diagnosis of attention deficit disorder, uh, where in adulthood, it was residual by DSM 3R. Uh, we could make a full diagnosis in, in adulthood and DSM-5 now, we're talking about 2013, um, the diagnosis of ADHD in adulthood. The DSM-4 criteria, 4 major criteria, they hold pretty much the same through DSM 5. Significant symptoms of inattention and or hyperactivity impulsivity, 6 of the 9, inattentive and or hyperactive impulsive for DSM-4. Symptom onset in childhood before the age of 7. Um, impairment from the symptoms. We have to have not just symptoms but trouble from the symptoms, two out of three domains of the individual's life, home, school, or work or social settings. And because comorbidity, as noted in our discussions today, is more often the rule rather than the exception. Um, so you have to be sure the symptoms and impairments are from ADHD and not something else. Here are the symptoms. Inattention, note that in DSM these are childhood domains and not adults. Um, the, um, DSM-4, DSM-5 will give you a list of examples to discuss what these are like in adulthood, but here are the same symptoms for DSM-4 and DSM-5, careless mistakes, trouble sustaining attention, easy distraction, avoiding things requiring sustained attention, losing things and forgetfulness under inattention, under hyperactivity, impulsivity, trouble staying seated, fidgetiness. Excessive movement always on the go, excessive talking, interrupting, or intruding others. In terms of the prevalence, and we've been talking about this, 6 to 9% of school-age children, probably 8%, is the most common, um, estimate, and 2.5 to 4.4% of US adults. Uh, the presentation type, it's called subtype in uh DSM-4, presentation type in DSM-5. Uh, most common is the combined when you meet both the inattentive and the hyperactive impulsive symptom threshold, that's 70%. Primarily inattentive is 25%, and the hyperactive impulsive presentation is uncommon, less than 5%. The male to female ratio. is higher in kids than in adults. Uh, it's 2 to 14 to 1, boys to girls and children, closer to 1 to 1 in adulthood. Um, and certainly in our ADHD program where we follow, um, uh, over 200 adults with ADHD, our gender split is pretty much even. And in part this is due to a higher loading of the inattentive symptoms for all adults and more so for women who carry a higher burden of the inattentive symptoms. About 50 to 60% of patients diagnosed in childhood go on to exhibit significant symptoms and be diagnosable in adulthood. And notably from the WHO studies, the prevalence is similar, not identical, but quite similar cross-culturally. East-West developed and undeveloped, um, running anywhere from 1.9 to 5.2%. I put these up here, not that you should get any of these scales, just so that you know, there are a number of diagnostic scales, including the CdI, uh, the Brown diagnostic scale, our scale is the ACDS. Um, there is also the DEIBA. Um, so, these are the diagnostic scales. Uh, if you're gonna use a diagnostic scale, they do require training to some extent. Uh, I'm not gonna go into them extensively, but you've had this in your slide kit. There are symptom scales that are broken out in terms of whether they um uh assess symptoms on the basis of the clinician assessing symptoms or their self-report scales like the ASRS. Um, these also break out in terms of whether they assess symptoms on a frequency basis, which is more common for the self-report scales or on a severity basis in terms of the, uh, intensity of the symptoms, um, as noted by the clinician. Those are clinician-based scales commonly. So there's a, and they also differ in whether they include co-traveling associated symptoms as a sort of subset of the symptoms. So, the Brown scale, the Connor scale, the, the RD scale, which has a lot of emotional dysregulation symptoms, the ADHDRS, um, and the ASRS which is available on the NYU website, and our, uh, semi-structured AISRS which is, um, used in many, many clinical trials. And has full prompting with about 8 to 10 clinical questions to ask about each ADHD symptom. Now, we're gonna talk a bit about the associated symptoms in ADHD now. Executive function deficits are higher level cognitive problems that involve response inhibition, nonverbal working memory, verbal working memory. These are all defined by Russ Barkley. And these are really um trouble organizing yourself and your environment, um, also the regulation of emotion and motivation, planning and problem solving, so procrastination, trouble with task initiation and completion. All of these things are part of executive function deficits, which are not a part of the core DSM diagnostic criteria, but commonly, as I'll show you, commonly co-travel with ADHD. Another set of symptoms are a set of dysregulation of emotion. Now these are not formal mood disorders, but it's rapidly shifting affective disturbances. So it's a lability of mood. It's an overreaction to environmental stimuli, whereas formerly in a mood disorder, the mood disruption occurs independent of the context and the stimuli. Here this is very much an overreaction to something that happened. Um, and this is defined as either emote EC or ED, um, and it's been used in a variety of different terms, but we'll call it deficit, we'll call it emotional control or emotional dysregulation in this talk. Now why am I talking about this? Uh, so one thing that's important is to understand that for adults, as compared to kids, the inattentive symptoms are more common than the hyperactive impulsive ones. This is old data out of NGH from Milstein where they looked at 149 consecutive presenting adults with ADHD. They did significant symptom counts and the inattentive symptoms were twice as common as the hyperactive impulsive ones. So, we went back and looked at this in the um NCSR study, uh, which was community-based and with a managed care sample, and here we validated this again, finding that the inattentive symptoms were 50% more common than the hyperactive impulsive ones. However, when we went ahead and looked at the symptoms of executive function deficits, they were equally common as the symptoms of inattention. And the emotional discontrol symptoms were almost as common as the hyperactive impulsive symptoms. So it's really important to understand that these co-traveling associated symptoms, which occur in other disorders besides ADHD, um, like mood disorders. Um, and, uh, they, they also occur in PTSD to some extent, um, but these are not part of the diagnostic criteria, but they're very common and they're important for you to understand because they can cause significant impairment, and if you don't ask your patients with ADHD about them, you may be, um, missing part of what's causing their difficulties. Another set of co-traveling symptoms are symptoms of sluggish cognitive tempo where patients, as defined by Barkley have 9 sets of symptoms that include daydreaminess, trouble staying awake and boring situations, confusion, easy boredom, lethargy, slow moving. Those symptoms also co-travel in ADHD. All right, so we've talked about what happened in DSM 4. When we moved to DSM 5, there were a couple of changes. The age of onset criteria changed from 7 to 12, as we talked about in our ask the expert session. We also, um, reduced the number of required symptoms, significant symptoms from in adulthood, from 6, inattentive and or hyperactive impulsive to 5. They took out the comorbid autism spectrum exclusion. So now, as we've had a whole session on, on ASD and ADHD. They required the symptom onset in childhood to be multi-dimensional, and they changed subtype to presentation, and they gave you some examples, but notably, the associated symptoms we've been talking about are not part of the diagnostic criteria. OK. Why is it important to make this diagnosis of adult ADHD? Adults with ADHD or are undiagnosed or twice as likely to be arrested or or divorced, 4 times as likely to contract a sexually transmitted disease, probably from not practicing safe sex. Um, they're more likely to be addicted to tobacco with uh lower quit rates, and they're more likely to be unemployed and underemployed. Driving is a major concern. Um, traffic violations and, um, motor vehicle accidents, this is data from Russ Barkley, are more common. And ADHD uh patients than, than controls, and when you put ADHD patients on driving simulators, they're more likely to speed, um, and, um, also have uh false braking, and they'll accelerate into critical incident. Let's say when they see a tree in the road. So this is one way you should always ask your ADHD adults about their driving problems. Not all of them have them, but if they do, it is important for you to be sure that they're treated um at the time when they're, they are driving. So, why is this somewhat complex? We did talk about the nature of the um dimensional quality of ADHD and that the core symptoms of ADHD happen in all of us. Impairment is critical, comorbidities are common. And the ability to diagnose impairment and can be difficult for very high functioning adults and under uh underperformance, um, and relative impairment, it does count. And so, uh, you shouldn't just dismiss the high functioning adult. Um, who is underperforming in certain significant domains of their life just because in other domains, if they're functioning in the workplace with support, uh, they can still be underperforming in other areas and, and merit the diagnosis. We've talked about the retrospective recall of childhood symptoms, and although we've talked about genetics today and a bit about neuroimaging, there is no one test, no neuropsychological test, no uh genetics test that will make this diagnosis and replace your careful clinical evaluation. This is uh the MTA study. I alluded to this, looking at, this is Maggie Sibley's re-evaluation of the adult-onset cases. I alluded to this and they asked the experts, uh, that most of the cases who were presenting with adult onset ADHD actually um had adolescence and late had onset and late adolescence, or they had a comorbidity. I put this in here about uh PCP perceptions of adult ADHD. We've done a number of surveys of PCPs over the course of time. Um, here, this is a survey of 400 PCPs, um, who treated a lot of patients with ADHD with ADHD, bipolar disorder, or anxiety disorders. They were, uh, much less knowledgeable about making an ADHD diagnosis than anxiety or depression. And they didn't receive as much instruction. Now, through some of the studies that Dr. Feron and I have been doing with quality measures, some of this needle has moved a bit where the understanding and recognition of ADHD is somewhat better, but the comfort level and treatment for adult PCPs has not improved all that much. In terms of comorbidities, personality disorders, depressive disorders including chronic depression, bipolar disorder, anxiety disorders, and substance use disorders are critical and highly common in adults with ADHD. I put this in here. This is data out of the MGH group. It is the original Berman uh sample that Doctor Ferone was involved in. This is the referred sample. It used to be felt that in some ways, the high levels of comorbidity seen in the, in the sample was due to the referred nature. And the reason I put this in is I highlighted the anxiety disorders here, but there are high rates of mood disorders, substance use disorders, personality disorders, and anxiety disorders in the MGH referred sample. When we looked at the NCSR data, again, the same high rates of mood, anxiety, and substance use disorders in the community-based sample that we did in the national comorbidity uh re-examination with Ron Kessler. So it's not just that the patients were being referred in. This is from the community data. These high levels of comorbidity exist in patients with AD adult ADHD. In terms of bipolar disorder, this is data from Andy Nierenberg and Mass General. If you have the, the dual comorbidity of ADHD and bipolar disorder, um, the onset of ADHD is earlier and more significant with more hospitalizations for your bipolar disorder if you have both disorders. This is data uh from Tim Rawlins that summarizes um some of the findings on substance use disorder and ADHD. Nicotine can be a gateway to other substance use for always assess this in your adolescents or your young adults. Um, nicotine does enhance attention. The young adults who had ADHD had earlier onset of nicotine dependence. There's always a question of what happens when we give stimulants to young adults and adolescents. Are we actually increasing the potential risk for substance use? And actually, the meta-analysis clearly show that we're lowering the risk of substance use when we treat the ADHD with stimulants, and we did talk about misuse and diversion. The most common uh misuse and diversion occurs with the use of immediate release mixed amphetamine salts in adolescents and young adults. Be very careful when you have patients requesting that in that age group. This is data from a factor analysis that we did with Ron Kessler and looking at the NCSR sample, trying to identify the loading of symptoms and the clustering of symptoms in adults with ADHD. I put this in here cause it talks about the associated symptoms of executive function deficits and emotional discontrol. And what we found here in terms of the factor analysis, we broke out into 3 different factors which are highlighted here. Which was an executive function factor, and an attentive factor and an impulsivity factor, the emotional dysregulated symptoms tracked separately, and that's an important thing that you'll be hearing fairly consistently about how they load and track, and they actually respond less to treatment overall. In terms of our scientific understanding, you saw this very slide from Steve earlier today about the number of candidate genes we do not have one candidate gene. Um, the high rates of ADHD, think of it as a familial, uh, disorder that tends to run in families where child relatives of adults with ADHD have higher rates of ADHD and adult relatives of children with ADHD have higher rates of ADHD, and the molecular genetic findings as summarized by Doctor Ferone for kids and adults are actually quite similar. OK. Let's get on to some of the neuro neurobiology. If we think about uh the neurobiology, we'll understand how the medicines work, and then we can go on, um, and talk about, uh, from the neurobiology, actually how the medications work. This is a catecholamine neuron, pre-synaptic, post-synaptic. Here are the, uh, the dopamine and norepinephrine transporters. These are vesicles for dopamine and norepinephrine, and here are the receptors and the post-synaptic synaptic neuron. OK, here are how our drugs work. And our stimulants, amphetamines and methylphenidate tend to block reuptake. At the transporter. Our selected norepinephrine reuptake inhibitors are non-stimulants that are approved in adults with ADHD. Anamoxetine and Voxazine block the norepinephrine transporter. Amphetamines are more potent than the methylphenidate stimulants, because in addition to blocking reuptake, they increased vesicular release of dopamine. You remember this, you'll remember how the drugs work, and then you'll be able to understand their potency and their clinical effects. OK. So, in terms of standard pharmacotherapy, Stimulants that are approved for adults with ADHD are, um, are the sustained release compounds generally. Um, and there are two major classes, the methylphenidate compounds and the amphetamine compounds. There are two non-stimulant compounds which are not scheduled, and they are approved for, um, ADHD. They're selected norepinephrine reuptake inhibitors, amamoxetine and Voxazine. Alpha 2 agonists. Um, are approved for kids and adolescents, guanfacine extended release, um, and clonidine is approved for, for kids. Um, however, I will say that there's a Japanese study, um, in where, um, guanxine extended release is approved for adults. It's not. Approved for adults in the United States. When I review these compounds, I'm going to review them from the meta-analysis and talk off of these those slides, so we have the capacity not to show you a lot of the individual studies because I want this discussion of medications to be bias-free. OK. This is from Steve's article in Nature Reviews and Disease pri uh primers. It's really a great article. So he goes through all the different medications. And all the background on ADHD. Note that there are immediate release forms of, of amphetamines. There are which come in um racemic and um and uh isomer forms and extended release forms. So there's mixed amphetamine salts, immediate release, extended release. The immediate release will last 4 to 6 hours, the extended release up to 12. There is a prodrug, which is Lisdexamphetamine. Um, that is Um, that is the amphetamine bound to an amino acid. The active drug is not released until it is cleaved, um, and the lysine is taken off and the Damphetamine is absorbed into the brain. Duration here noted 13, it actually can be slightly longer. Um, there is a triple-beaded, the 3rd bead on mixed amphetamine salts. Um, that duration can be up to 16 hours. In terms of the methylphenidates, most methylphenidates, if you're just writing for Ritalin, methylphenidate, it is a, uh, racemate. It's equal amounts of ENL methylphenidate, will last 3 to 4 hours and it's immediate release preparation. Sustained release preparations are either in barrier forms that can come in intermediate. Uh, deliveries which can last 6 to 7 hours or up, uh, up to, up to potentially 8, or in, uh, beaded preparations, which you can, let's say methylphenidate LA, short and long-acting beads, which can then last 2 released beaded preparations, 2 released forms of methylphenidate that will last. Potentially 8 hours. Um, an osmotic release form, um, which can last up to 12 hours. Um, and there is demethylphenidate. Dmethylphenidate is the active form of methylphenidate, is the isomer. Um, it tends short-acting form, it's slightly longer acting than the immediate release methylphenidate. Um, and it does come in an extended beaded release form, um, that, um, will last up to 12 hours, and it does come in a pro-drug form, which is serex methylphenidate, dexmethylphenidate, which can last up to 12 hours or longer. Um, so, here's the review of all of the, uh, stimulant preparations. Then there are two non-stimulants which include anamoxetine and Voxazine. So, this is from Sam Cortese's uh Lancet 2018 review. I put it up here cause it's, I like the, the forest plots that uh we have from this one. This has been followed up with subsequent meta-analysis, most recently this year, but I happen to like the way and the data pretty much holds. So, here we We looked at all the data, um, looking at change in ADHD symptoms in kids and adults, and it's quite similar, except that the efficacy of methylphenidate compounds was slightly greater in kids as compared to adults and the efficacy in amphetamines was slightly greater compared to side effects in um in adults versus kids. Um, but note that all of that, anything that's on the left-hand side that favors, favors the drug, anything on the right-hand side, um, does not favor the drug. And note, the modafinil, um, did not favor the drug and modafinil studies, there were several, did not pan out, and it is not, uh, should not be used first or second line in adult ADHD is really reserved for third-line use. Here are the teacher ratings of kids. Adverse events, um. And all of these compounds work, so that's really important to keep in mind. And another thing to keep in mind is that the magnitude of effect in kids of the stimulants and of the non-stimulants is somewhat greater. Um, is about actually twice as large as it is in adulthood. The side effects of the stimulant trials are actually quite similar for both methylphenidate and amphetamines. You have to look at dry mouth, insomnia, we've talked about, appetite suppression that uh will occur over the course of time, headache, edginess. They're generally fairly neutral on ticks, but they can exacerbate ticks. Uh, psychotic symptoms have been something especially noted in a recent, recent inpatient trial. They're uncommon, but you have to be aware of that. And cardiovascular effects, the average change in blood pressure is 3 millimeters, mercury, 5 beats a minute and the heart rate, all the same for all of the classes of drugs. And remember, those are averages. So therefore, blood pressure and pulse in some patients will go up more than that, and they should be monitored during the course of treatment. Anamoxetine, side effects, um, the side effects of the effect size of anamoxetine. Is, is less than that of the non-stimulant effect size is somewhat is less than that of the stimulants, similarly for Voxazine. So, dry mouth, insomnia, with an amoxetine, you will get some um libidinal or erectile difficulties which may be somewhat less than Voxazine. Um, and Voxyzine does seem to have some preclinical uh serotonin effects, which will be important for us to discuss later on. And as I mentioned, the blood pressure and pulse effects are similar in anamoxetine as they are in the cardiovascular effects. OK. So There really were not a lot of long-term studies, and there still aren't a lot of long-term uh data for these medicines and adult and adults with ADHD. All these medicines were helpful except for modafinil in adults, all better than placebo. As I mentioned, the medicines in adults were less efficacious and less well tolerated than what we found in kids. Overall, methylphenidate was more superior in kids than amphetamine in adults. The amphetamine effect size in adults is generally um quite large, anywhere from 0.7 to 1.0 with methylphenidate somewhat less and the non-stimulant effect size, about half, OK. Uh, this review was done prior to Voxazine, more recent amphetamine and methylphenidate and, uh, guanfacine extended release data. OK. Now we're gonna get talking a little bit about the effects of the stimulants and the non-stimulants on these associated symptoms. This is a study that we did and published on um Lisexamphetamine, the prodrug on executive function deficits. Patients were randomized. The treatment with Lisexamphetamine 30, 50, 70 versus placebo. They were all adults with ADHD and they also had to have executive function deficits as diagnosed on the brief. So Lisa amphetamine was effective in treating these executive function deficits, and this is the brief GEC which is the overall score, um, versus placebo. But what I wanted to point out, when you look at the subscales on the brief, they all improved, OK. And, here's the noted effect size. But the one that wasn't significant and the one that improved the least was emotional dysregulation. So just keep that in mind. It's a theme that you're going to hear over the course of time. So when we look at emotional dysregulation, there have been a number of studies that have looked at different agents that have found that stimulants can try to treat these. Fred Reimer looked at oral methylphenidate. There was a study from Rossler and his group at at uh oral methylphenidate extended release. Marchant looked at two different preparations of methylphenidate. Um, Wender again, looking at methylphenidate IR and we had published twice on Lisexamphetamine. But overall, the magnitude of the effect is somewhat less on emotional dysregulation. Non-stimulants have been looked at too. Um, um, Wender looked at bupropion. Hedges looked at venlafaxine. Marchant looked at anamoxetine. We published on anamoxetine and emotional dysregulation. The Acheson review here is quite notable in that the overall effect on emotional dysregulation is also shown to be less, and we published on an anamoxetine 2 times. So, in summary, when you look at the pharmacotherapy for executive function deficits and emotional control, these overall effects on executive function is about half the effect we see overall on these core ADHD symptoms of inattention and hyperactivity impulsivity, and the effect size and emotional dysregulation is even less. OK. This is a study that we did in conjunction with Jack Newkorn's group at Mount Sinai. Uh, we looked at patients in two different ways. We assessed for symptoms of ADHD and sluggish cognitive tempo. Um, and we treated them with Lisex amphetamine versus placebo. It was a crossover study with a 2-week washout, uh, looking at sluggish cognitive tempo ratings and ADHD ratings. And here's the patient allocation throughout the trial. Um, we randomized 39 patients, um, and one was excluded from inconsistent reporting, so 38 patients in the analysis. And what we found was, when you looked at the ADHD ratings, significant improvement in this sample that had both ADHD and slugg sluggish cognitive tempo. Um, here you see the drug effects. Here you see the um drug effects and this is the group that got drug first. And this is the group that got a placebo first. But there were some carryover effects in the group that got, um, that got lisdexamphetamine first. So, um, we had to show them separately here because this, this group did not get back to baseline. And notably, So this, this is the sluggish the tempo ratings that I was showing you, and similarly, here are the ADHD ratings. Both got better. So when there was comorbid ADHD and sluggish cognitive tempo, um, they both got better with Lisexamphetamine versus placebo. There wasn't a water effect with a larger placebo effect in group block 1 versus versus 2, in spite of the two-week washout, they didn't get back to baseline. This really was the first time we looked at the effects of stimulants in adults with ADHD. And the other thing I want to point out, and this is for future studies, only about 25% of the change in sluggish cognitive tempo ratings when we did regression analysis was due to a change in ADHD symptoms, which showed that the sluggish cognitive tempo may be a true co-traveling symptom, um, similar to executive function deficits rather than a core symptom of ADHD, but much more to come on that. We really don't have all the data on that. Couple of notes on the stimulant shortage for those of you who've been taking care of patients. With ADHD, this is data from the CDC looking at uh stimulant prescriptions going into the pandemic, and what you see are that stimulant prescriptions are going way up, uh, for women. And Here are women, here are men, stimulants are just going up, starting in the pandemic. Of note, this is data looking at um stimulants and non-stimulants from a commercial database, and IQVIA's database, and it wasn't just stimulants that went up here, it was non-stimulants too. So it's um the pandemic had effects, but more patients with ADHD were being driven into treatment. Back to discussing misuse and diversion, we can't talk about it enough. The short-acting stimulants we have to remember are not approved for adults with ADHD. Just sustained release preparations. Be very careful about patients who insist, young adults who insist on receiving immediate release mixed amphetamine salts. We really tend to recommend first line treatment. If you're gonna use a stimulant to use a sustained release, uh, stimulant or a non-stimulant for an adult with ADHD. Um, always check your, the, it is mandatory. Uh, to check the ISOP database for those of you prescribing in New York, and you should check databases whenever, uh, possible. Always get collaterals. These are ways of trying to diminish, um, misuse and diversion, and also document impairment whenever possible. So now I'm gonna show you some newer data that we've collected, um, that will focus somewhat on, uh, looking at associated symptoms. We have about 8 minutes left. I think we finish on time. This was a six-week study with a 2-week, uh, single blind placebo lead-in of triple-beaded mixed amphetamine salts, that's Maus in 18 adults with ADHD. Uh, we looked at clinician ratings, self-report ratings, effects throughout the day. Impairment and its effects on executive function deficits. Significant effects from the amphetamine salts. On clinician ratings of overall ADHD. And you see a significant effects on the impairment on executive functions. Um, and one thing I, I will just say that it's the overall effects on executive functions measured on the brief are just somewhat less. You can also measure effects of early in the day, late in the day, and very late in the day across the treatment, uh, paradigm, and we were able to show significant effects of those three-time measures. So this trial was conducted during the pandemic and ratings were done actually remotely, which is of interest, uh, showed significant effects on the, on executive function. Um, and we did not find much of a change in the single blind placebo lead-in, and we've moved to much more of a stabilization phase in our, our clinical trials to allow patients to have 2 weeks, 1 to 2 weeks to stabilize their ratings, um, and a way from actually leading in with a placebo. This is a study we just completed and published on erex methylphenidate, dexmethylphenidate, and adult ADHD. It's a pro-drug methylphenidate compound. Uh, trial design was a stabilization phase, followed by 5 weeks of open treatment. 17 participants entered the observation phase, 15 were treated in in the actual active treatment phase. Here's what the patients look like. And overall, there were significant effects um, um, across um self-report and um clinician reports, but I will say emotional discontrol ratings are, are just not um as robust um as other measures. So emotional control ratings are not changing quite as much. And we were also able to show the drug was fairly smooth in its effects throughout the day. We have a smoothness measure. So it was generally well tolerated. Uh, the, the blood pressure changes were somewhat larger, uh, than other stimulant trials, but, um, and that narri's, uh, looking further, uh, and that the changes were, um, in systolic 8.9 and diastolic 4.4 mill is made of mercury, but it was a relatively small sample. Centinnaidine is a triple reuptake inhibitor. Um, this is the registration study, 859 patients from two studies, 200 mg a day versus 400 mg a day versus placebo, AISRS versus CGI and what you see is, so this is a norepinephrine. Um, dopamine serotonin reuptake inhibitor of note, Osua has given an unrestricted educational grant to support this CNE activity, but has no control over the presentation of content. Here we're showing from both studies. For the ADHD scores and you see significant effects of both doses of sapidine. This medication has been filed for approval but is not currently on the market. And similarly on the CGI ratings. The other thing I wanted to show you was uh the data on meaningful change. The meaningful, this is a poster presentation from the APA last year, um, looking at 18-point change on the AISRS and significant effects of both doses of um cenaidine 200 and 400 mg. Boxazine ER is a selective norepinephrine reuptake inhibitor with preclinical 5-HT effects. It's approved for ADHD. Most notably, this is a, um, uh, uh, there's a study we presented at the APA last year. It's a central decentralized trial with training graders. It's different from a randomized clinical trial. 161 patients, 15 weeks of Voxazine, 200 to 600 mg a day, and These patients all had some symptoms of depression and anxiety, and some had depressive and anxiety disorders which were not the main focus of treatment. The ADHD was. What's kind of interesting is you found significant effects on um AISRS patients reported um and um the ASRS OK, looking at um the overall effects on clinician and patient reported symptoms. But when you look at the anxiety ratings and the depression ratings, they were significantly improved also. And that's a notable finding actually. And finally, I wanna show you uh some findings from a study of uh a prism neurofeedback, which is a neurofeedback targeting amygdala act down regulation of amygdala activity. This is a pilot study that we published recently. Um, it's a specific type of nerve feedback that, um, develops an electronic fingerprint from developed from EEG signals validated with FMRI. We don't put patients in the, in the scanner, but they have an EFP biomarker. And the patients are training to have avatars sit down and learning how to regulate their emotions. Um, they have 15 sessions over 8 weeks. Each session has 25 minutes divided into 5 cycles, and our total outcome was the DSMAISRS score. Uh, 9 patients. Uh, 2 dropped to 1 after 5 weeks, 1 after 7 weeks. And the effects were pretty dramatic. Large changes in their overall ADHD scores and their executive function measures and their emotional dysregulation measures. I should note that traditional forms of neurofeedback that target areas in the brain involved in attention have not been shown to be in large scale studies, placebo-controlled studies. Now, this was an open pilot study. We put in an application to do a controlled trial, um, but the traditional form. And neurofeedback have not been shown to be helpful in, um, in ADHD. And it, this shows that that the patients were able to, the participants were able to regulate, down regulate the amygdala-defined signal, so they were able to train and do regulate the signal. Meta-cognitive therapy is a specific type of psychotherapy that's approved for adult ADHD. This is Mary Cellanto's uh uh study looking at meta-cognitive therapy versus supportive therapy. Significant effects of meta-cognitive therapy over supportive therapy. It should be noted that environmental modifications are quite important for adults with ADHD in terms of structuring their environment, organizing their physical space, using reminders to take their medicine and pay their bills and putting things on autopay. So in summary. ADHD is treatable in lifelong neurodevelopmental disorders. No shortcuts in making a diagnosis. Um, use running scales when you can. Psy medications and psychosocial treatments are, are helpful. Medication effects are greater in kids than adults. Both stimulants and non-stimulants work looking for comorbidity and associated co-traveling symptoms. Apsar is making guidelines for adults with ADHD. We have international guidelines from the UK and Australia, um, but we don't have them in the US for adults. And they're coming out in 2026, and I'll stop here. Published December 6, 2025 Created by
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