Dr. Otto Ratz: Hello. My name is Dr. Otto Ratz and I am a Managing and Medical Director of SynerMed Communications. I would like to take this opportunity to welcome you this live Web conference on Clinical Cases in ADHD; Spanning the Spectrum From Adolescence to Adulthood.

This educational activity is cosponsored by the Postgraduate Institute for Medicine and SynerMed Communications, and it is made possible by an independent educational grant from McNeil Pediatrics. Before we begin, let me take a few moments to go over the format of this program.

We will begin with a presentation by Dr. Timothy Wilens, who will briefly review the prevalence, etiology, and diagnosis and the lifetime course of attention deficit hyperactivity disorder (ADHD). He will discuss the comorbidities associated with ADHD, and utilize clinical cases to demonstrate various treatment options. After Dr. Wilens presentation, we will ask you a few polling questions.

After that, there will also be a question and answer session during which you will have an opportunity to ask Dr. Wilens anything you would like. You may submit your question at any time during the program via the button on the upper left on your screen. It is labeled "Ask a Question." At the end of the program, you will be directed to the CME posttest where, after correctly answering questions, you can obtain CME credit.

Now, I would like to introduce our presenter. Dr. Timothy Wilens is Director of Substance Abuse Services in Pediatric Psychopharmacology at Massachusetts General Hospital and Associate Professor of Psychiatry at Harvard Medical School.

Dr. Timothy Wilens: Hello and thank you. I would like to introduce the programs in a manner of going through a case, and then highlighting some of the salient features of the case in terms of some database information. All attempts through this Webcast have been made to give very contemporary information in this area as opposed to reviewing older literature. It is really trying to integrate some of the newest findings we have in the field along with some of the older findings to help us better integrate some of the conceptual issues that are underway in ADHD.

We are going to start with case one of Steve. This is a presentation of a 32-year-old married bartender, who frequently is off in the cash register count at the end of the night, but generally does well at work. He is a social guy, he is attentive to his customers, likeable, and enjoys his work.

His wife, however, is frustrated, notes that he is really unable to keep a checkbook, she has been taking over all of these issues, and he is forgetful. She no longer expects him to remember her birthday or anniversary. That is not a smart thing to do in a relationship. When he forgot or is late to pick up their child at daycare several times, she insisted that he go for evaluation, not very uncommon in terms of referral patterns.

The history is that this is a gentlemen who was diagnosed with ADHD combined type at 7 years of age, treated as a kid with twice a day MPH, methylphenidate. Methylphenidate twice a day for 6 years and discontinued in junior high school. He no longer thought he needed it, when he skipped doses; he no longer seemed to be hyperactive as when he was younger. So he seemed to grow out of it, and because of that he stopped the medication.

In the next slide, you really notice the chronicity of ADHD in terms of the different studies that evaluate it. But before I even go there, I would like to talk to you a little bit about the prevalence of this disorder. The data would indicate that the prevalence in the pediatric group is about 6% to 9% of children and adolescents have ADHD.

If you look at adults, recent epidemiologic data by Kessler and others have demonstrated about 4% to 5% of adults in this country have ADHD. It turns out that it seems to be a worldwide prevalence, so it is not true that it is just US-based. Statistically there is no difference between other countries and the United States.

But, what about the chronicity? Here we are talking about a gentleman who is grown up and had it as a teenager or as a kid and what about now? You can see that the chronicity of ADHD really varies. Some of the issues that come up around whether individuals grow out of this disorder are largely based on some of the differences in the literature. Anywhere from 10% to 90% of children will persist with the disorder into adulthood.

Why is that? A lot of that is methodologic, and if you look at the most contemporary diagnostics using the DSM-IIIR, remember we are in DSM-IV now, which really includes not just the hyperactive component but the attentional base component, functioning, et cetera, you see that there is more of a persistence of the disorder relative to the older definitions that relied more on the hyperactive component.

In fact, in the next slide, if you look at persistence of full and residual diagnosis, just to summarize this slide, if you are evaluating and examining what the persistence rate of ADHD is from childhood into young adulthood, here as indicated in this slide, if you required full diagnosis to all the criteria of the disorder, not only just the symptoms but other criteria, you see that a small percentage of adults actually continue to have the disorder if you follow these children into adulthood.

On the other hand, the same kids followed into adulthood, if you use a different definition where you say you may not have full criteria for the disorder, you may have a couple of symptoms short but you still have clear evidence of impairment, more symptoms than not, et cetera, really still making the criteria but more on the ADHD not otherwise specified category as opposed to full criteria, you will see that over 50% of the children yesterday continued to have the disorder into adulthood. So there continues to be chronicity.

And in the next slide you can see that. The hyperactivity-impulsivity, in specific on that, really there is a change from childhood into adulthood. You start getting less of this running around, can't play quietly, running, actually physically hyper, to an internal restless feeling, frustration, driving too fast, can't wait in line, that may not be pushing in line but maybe just avoiding lines.

Or road rage, butting into conversations, you can have both the hyperactive kind of physical hyperactivity, the internalization of that or hyperactivity that may kind of bleed into other categories such as impulsivity and some of the cognitive effects that we will talk about a bit later.

In the next slide, there are a number of screeners that really do help identify ADHD. And this is a 6-item screener that was developed partly out of the national comorbidity study, and then tested and worked on by the World Health Organization. You can see a Web site there that you can access it from. You are allowed to copy it and hand it out. But it is basically looking at six different items and based on how you score, and it is very simple to score, that would indicate that an adult may be suspicious for having the diagnosis. This is really a screener; it is not a full diagnosis in itself.

I think what is important in terms of the lessons learned from this case is that ADHD frequently persists into adulthood. So again, we estimate that at least half of children and adolescents today will continue to manifest the disorder into adulthood. Be alert to symptoms of hyperactivity that may appear different in adults than those in childhood. Children, again, are overtly hyperactive, manifesting kind of the classic hyperkinetic disorder of childhood.

You may see less of that in adults and more of an internalization of those symptoms. Or it may be manifested differently, or there may be major compensation and you need to ask about that. Stopping treatment based on the assumption that ADHD is always outgrown can have negative consequences. So you need to really evaluate as you are pulling medication away during adolescence, first, are the symptoms of ADHD really gone when you take the medicine away?

And if the symptoms are still there, is there still functional impairment related to those symptoms? Are those symptoms manifesting themselves in the child that is causing disruption in the way they are interacting with the environment and able to do their work, schoolwork, as well as socialization, et cetera?

I think it is also important in this case that you heard about to realize that the risk of untreated ADHD. And I think that blends to the first two cases, what happens if you do not treat ADHD, and what are the consequences? You are going to hear that over and over.

What I would like to do now is to move to case two, Jill. A little bit different now. Here, we are talking about a very young adult, arguably still — kind of an old adolescent, young adult. This is a 19-year-old sophomore at a large state university. She is having significant struggles with completing projects and test taking and is actually on academic probation. Now, Jill has no significant mood symptoms, smokes cigarettes and frequently limited alcohol use, no elicit drug use. So she has no real substance use disorders.

Now, this case, just to flag it, is bringing up the issue about somebody who is having problems now but what about her childhood? If you go to the next slide in terms of the history, Jill did pretty well academically throughout her earlier grades and high school, she did not have any behavioral problems. She participated in kind of a talented program in high school, but never really studied, was just really a bright kid who was able to get through, and also had a mother and father who were very attentive to her needs and helped steer her on what she needed to get done.

With the transition to college, her grades began to dip, with incomplete assignments, declining test scores. And looking back, when she did try to study as a younger kid, really was never able to do it more than a few minutes, but got by because she was bright and her mother provided the oversight. What we call sort of the executive secretary of Jill's brain was her mother. And there was a lot of structure around her.

That is an important aspect of ADHD. Structure is very important in ADHD, routine and structure. Very ADHD-friendly in terms of helping these kids in a very non-pharmacologic approach that really, you can see here, really benefited Jill in terms of her outcome as a high school student. But now she starts to fail, having lost some of that and also more and more burden and demand.

In the next slide, what we want to do is talk about some of the attentional components of this disorder. What we know is that attention dysfunction of ADHD tends to persist. That is a bit in contrast to the previous case where we talked about in some ways a decay or extinguishment of hyperactivity and impulsivity.

Here you can see that whereas children have many of the issues of sustained inattention, distraction, follow-through, organization, with adulthood you could start to see some of what we think of as a change in the symptoms, or kind of the impact of those symptoms on the interaction that the adult is now having with the environment: difficulty sustaining attention, procrastination, slow, inefficient, poor time management, disorganization. And you can imagine now an adult who has a lot of schooling or a lot of work burdens, really starts to develop difficulties with these issues.

In the next slide, we recently were involved in a big symposium on attention and deconstructing attention in ADHD. It was a very interesting one in terms of the fact that it is important to realize that inattention really lives in multiple parts of the brain. We are talking about ADHD as a cognitive deficit, that there is prominent attentional dysfunction in the disorder.

I can tell you that attentional dysfunction over time predicts a lot of problematic outcomes. We use to think it was delinquency or the hyperactivity-impulsivity. It turns out that attentional dysfunction really is a stealth risk factor for a number of things that you will hear throughout this program. But it lives in different areas of the brain.

You can see that there are different types of attention, like orienting and directed attention. There is vigilance and alertness that is involved and sticking on it, and the alertness aspects of attention; as well as what we refer to here more as the executive attentional organization system, including working memory and shifting and planning and disengaging and engaging and being able to complete and move around. And you can see aspects of all of these areas of attention that impact ADHD.

The case of Jill also, as you can see on the next slide, highlights some of the gender differences and important gender issues in ADHD. We know that ADHD prevalence among adults, if you look at referred adults with ADHD, is relatively similar. That is about 40% to 50% of referrals in the clinical trials, and this is multiple clinical trials now in adults, are women.

Yet, if you look at the preponderance of referrals into pediatric trials and in clinical practice, and even in epidemiologic studies, there are a lot lower rates of ADHD in females relative to males. And there is a lot of interest in trying to figure out what that is.

I can tell you that it used to be differences of 10 boys to every girl in the clinic about 15, 20 years ago, and that has now changed to about 3 boys to every girl. So I think we are much better at identifying it. I think that identification is part of this story. Boys tend to have more externalizing disruptive comorbidity such as conduct disorder or severe oppositional disorder relative to girls, and it may be that some referral issues may be leading to that.

In the next slide, another important point that is brought out by Jill is, what do you do now? If you are sitting trying to diagnose in this case a young adult or even an older adult, who comes in and says I have classic symptoms of ADHD. You get a track of the symptoms, but you do not get a classis track of those symptoms before the age of 7, which is required by the DSM for a full diagnosis of ADHD.

In a series of analyses done by Dr. Steve Faraone recently published, he looked at a number of areas between adults who had adequate current symptoms, and a track of the symptoms back before the age of 7, so they had classic prototypic ADHD, and a similar group of adults with ADHD who had current symptoms of the disorder, but the track of the disorder was not really classically before the age of 7.

For example, it would be 12 or 15, sometimes even emerging during college. The mean age of the sample, I believe, is around 38, so you had plenty of time to have a track of the symptoms. So in other words, I would say later onset ADHD, is it something we should even consider as valid.

What Dr. Faraone did in this case is looked at rates of co-occurring psychiatric disorders, like conduct disorder, substance use disorders, generalized anxiety disorder, learning disorders. He also looked at likelihood of having a family member with the condition and neuropsychological profiles. What he found was that the groups of ADHDs who had the full onset of ADHD, classic prototypic ADHD, looked very similar to those who had late onset ADHD where the onset was a little bit later.

He really called into question commenting that probably these later onsets where it is hard to get a classic track of the symptoms of ADHD, like Jill's, are probably a very valid form of ADHD. We have also shown in separate studies that they respond similarly to pharmacotherapy.

So the lessons from case two are that ADHD may go unrecognized in children whose behavior does not call attention to their symptoms. In this case Jill didn't have a lot of externalizing stuff going on, was doing well. Why would you know? Girls may have ADHD as frequently as do boys, but because theirs is maybe less likely to clause disruption, it is not diagnosed.

In this case, I am not sure Jill would have been diagnosed anyway. It would have been hard to know. And for individuals whose ADHD is not identified and treated early, the removal of structure and support in adulthood may cause an inability to function efficiently. And then, you may see that interaction [effective] that problems that the individual has related to ADHD manifest.

So again, stay tuned in this whole area because we are going to learn a lot more. This is also somebody where rating scales may be helpful. And again, you may not be able to firmly diagnose it as the diagnosis of ADHD prototypic, but maybe ADHD not otherwise specified with the time of onset.

By the way, this also applies to adolescents where you have a bright adolescent, typical age of presentation is 14 to 15, where when they first show up in the clinic or even being followed by a pediatrician for a number of years. The pediatrician will say I never knew that these problems existed and now all of a sudden they are coming to my attention, what is going on. Well, maybe that the child compensated, the parents compensated, the system compensated and now they developed it.

We are going to move forward now to case three, which is Juan. This is a 38-year-old divorced manager, not uncommon to have a divorce or separations in these individuals, recently diagnosed with ADHD. He had the combined subtype. He was initially treated with OROS methylphenidate, 36 mg for 1 month, with noticeable but a limited benefit, about a 25% reduction on the ADHD rating scale.

It was very good that the person was using rating scales, not mandatory but helpful in monitoring treatment. Subsequently, he was treated with extended-release mixed salt amphetamine, 20 mg, again roughly the same response. And in light of his age, his family practitioner, who was bold to make the diagnosis and treat, was reluctant to push the dose any higher.

In the next slide, it really taps into the diagnosis of the disorder in adults. And there are a number of different rating scales that can be used. Do you need to use a rating scale? You do not need to use a rating scale, but use of rating scales can help you in terms of making you more comfortable with the diagnosis, also the patient.

Sometimes if the patient completes a rating scale it is not your subjective "rushed" opinion of what occurred, but the individual endorsed the symptoms themselves. They had plenty of time to complete it, they can think about it, they can go back and get ancillary information if necessary.

Now, some of these are diagnostic rating scales and some of them are symptom assessment instruments. So some of them are helping you with the diagnosis of the disorder, for example the Connors Adult Diagnostic Scale, the Barkley's Current Symptoms, the Brown ADD Scales, the Kiddie-SADS Modules, et cetera. Some of them are symptom assessment just to help you track how somebody is doing with treatment.

You just ask them to do it when they first come in, and then once you get to what you think is a reasonable dose, have them fill it out. It takes just a couple of minutes, you score them instantly, or you can actually look and just get a sense of what is better, what is not. And that gives you a quantitative outlook on how somebody is doing.

Also it is used in measuring improvement with treatment. You will see in some of the trials that we report that that is what we are using, is how much improvement do you have on the ADHD rating scale, the Connors Rating Scale, whatever. A lot of people ask which one is the best. I think they are all good. Using any one of them I think is terrific. Some of them cost money, some of them do not. They are all based on the DSM-IV criteria of the disorder, really the 18 core symptoms of the disorder.

When we talk about treatment options for adults, we know — on the next slide, we know that cognitive behavioral therapies, first of all, can be useful adjunctively with the treatments; there are really no studies of structured psychotherapies in adults in ADHD who are untreated pharmacologically. So we do not have those data.

The current guidelines, albeit really not as formal as we should have at this point, recommend, after a thorough diagnosis, consideration of medications. The medications that we have available are both the stimulant and non-stimulant class of agents.

Among the stimulant medications we have methylphenidate, both the racemic dl-methylphenidate, the d-methylphenidate extended release, which is FDA approved, and the mixed amphetamine salts XR, which is also FDA approved, and lisdexamfetamine, the new amphetamine prodrug that is to be released soon.

The non-stimulant medications are atomoxetine, which are FDA approved, and then the older tricyclics, which have been demonstrated in smaller studies to be effective, and bupropion. Here you can see the typical dosing for these medications and the common adverse events that have been reported in clinical trials or indicated in the package inserts.

To give you a sense of the kind of outcome one can expect, if you look at the next slide for dexmethylphenidate hydrochloride, which is Focalin^® XR, this is one of the extended-release preparations. This is a fixed-dose, 5-week trial with adults with the mean age again 39, very common, about half male, half female. Here was a dose ranging study; you were either assigned to 20 mg, 30 mg or 40 mg.

At the end of the trial, you can see if you look at the percentage of reduction in the ADHD rating scale, you can see that there were significant improvements at 20 mg, 30 mg, and 40 mg of the dexmethylphenidate XR compared with placebo. The highest dose, the 40 mg, probably gave you the biggest reduction in symptoms relative to the two lower doses.

There was no clear linear dose response, that is 30 mg was better than 20 mg and less than 40 mg. Because of that, the FDA-approved dosing was really capped at 20 mg in adults. But again, this study gives you at least a sense of what to expect in terms of percent reductions in the ADHD rating scale, roughly 65% response rate.

In the next slide, you can see there are improvements, and this is with OROS methylphenidate now Concerta^®. Again this is not FDA approved, but it has been studied. This is a large study looking at improvements in the one of the rating scales, the AISRS. This is the percentage of subjects who had a 30% reduction, which is a — the older definition of response in that roughly it was standard deviation change.

You can see over 75% of subjects in this trial, the mean dose of 87 mg a day had a reduction in their AISRS, one of the rating scales of ADHD. And again, if you use 30% reduction plus an overall impression of improvement, you're at around 65% to 70% and [that is same too as a] 50% reduction.

So these are different ways of looking at outcome, at the percent responders. And again, you're between 60% to 70% response rate with this medication at again roughly 87 mg I believe was the mean dose in that study..