® on the treatment landscape for the management of ADHD, attention deficit hyperactivity disorder. I’m Dr Theresa Cerulli, from Beth Israel Deaconess Medical Center in Boston. I’m excited to announce that I’m being joined today in this discussion by 4 of my esteemed colleagues and ADHD experts: Dr Ann Childress, from the Center for Psychiatry and Behavioral Medicine in Las Vegas, Nevada; Dr Andrew Cutler, from SUNY Upstate Medical University, Lakewood Ranch, Florida. We also have Dr David Goodman, from Johns Hopkins University School of Medicine. And finally, please welcome Dr Timothy Wilens, from Massachusetts General Hospital in Boston, Massachusetts.

Our discussion today will focus on currently available therapeutic options to treat adult ADHD as well as newer agents in the pipeline with novel mechanisms of action. Let’s get started.

David, it would be great if you could get our group rolling. Tell us, what is ADHD? Is it different from ADD [attention deficit disorder]?

 ADHD is the formal diagnosis. Without hyperactivity and impulsivity in adults, the general public will call that ADD, but ADHD is the formal diagnosis. It breaks out into 3 flavors, as I like to call them. You have the inattentive, you have the hyperactive and impulsive, and then you have the combined type. What’s interesting is that from DSM-IV to DSM-5, we’ve gone from subtypes to presentations.

That’s because the children who might have had hyperactivity and impulsivity and would have been a combined type as a child may now be an adult with less hyperactivity and impulsivity. They don’t reach the symptom threshold for a combined type, and they get diagnosed as inattentive. We now go on presentation of presenting symptoms when you see the patient for a comprehensive psychiatric evaluation.

 And those presenting symptoms are a little different for adults, in terms of diagnostic criteria and changes from DSM-IV to DSM-5?

 Well, there are several changes. The DSM-IV criteria had a threshold of age 7. We’ve increased that to age 12, because a lot of the inattentive children weren’t being diagnosed. A lot of the focus was on disruptive behavior. However, as the children age, the inattention and disorganization become the source of the impairments, along with executive function.

And so, the evolution from childhood to adulthood. And my area of expertise is in older adults, looking at the trajectory of the symptoms over the course of time. But coming back to DSM-5, you have the symptoms. The symptom threshold has changed for children and adults. For children, it’s 6 of 9 inattention or 6 of 9 hyperactive impulsive symptoms. For adults, it’s 5 of 9 in either of the 2 categories.

So you have the symptoms, you have the impairments that they need to cause. Because you can interview somebody who says, “I have occasional inattention and distractibility,” that doesn’t mean you have a case of ADHD. Remember, the hallmark of ADHD is the foundation of symptoms in childhood and early adolescence that evolve relatively unchanged over the course of time.

Clinical Subtypes of ADHD

 What about the prevalence and clinical burden of this disorder? Ann, what are the statistics on this?

It’s a little different in children versus adults, and it really depends on what source and what country you are looking at. A recent meta-analysis calculated the worldwide prevalence of ADHD [attention deficit hyperactivity disorder] in children to be about 7.2%, but it’s a bit higher in the United States. As part of the 2016 National Survey of Children’s Health, parents reported whether their children—aged 2 to 17&mdash;had ever received a diagnosis, and it totaled about 9.4%, or 6.1 million children who had received the diagnosis at some time in their lives.

Currently, 5.4 million children have the diagnosis. That’s almost 90% of the children ever diagnosed. Two-thirds are currently taking medication, and almost half had received behavioral treatment for ADHD in the past 12 months. In contrast, 23% had never received medication or behavioral treatment. If you look at adults, the World Health Organization estimated the worldwide prevalence of ADHD in adults aged 18 to 44 to be about 2.8%. In the United States, it’s a bit higher—about 4.4%.

 It’s interesting to hear those differences. How about other differences? Men versus women, and boys versus girls, in terms of the ratios? What does that look like, Ann?

More boys are diagnosed than girls. And if you look at adult males, it’s about 1.6 to 1, regarding the prevalence.

 Tim, with years of research experience from Massachusetts General Hospital, what are some of the factors that predispose children and adults to having ADHD? Is there a genetic link?

 Yeah, absolutely. In fact, this runs in families. But just because it runs in families doesn’t mean it’s necessarily genetic. So it turns out three-quarters of cases are thought to be genetic. Just to give you a sense, they call it heritability, but it’s pretty close to autism, schizophrenia, and some of the disorders that we know are highly genetic. But saying that the heritability is about 75% would also indicate that about 25% of cases are from other causes.

We think 1 of the most preventable causes of new onset cases is in utero exposure to smoking, just good-old cigarette smoking when somebody is pregnant. We think 10% of cases of ADHD may actually be caused by that. In terms of prevention, that’s 1 way to help prevent ADHD.

If a parent has ADHD, we estimate that 25% to 50% of their offspring are going to have ADHD. That’s similar to if you have a sibling who has ADHD. Let’s say the first child has ADHD. A parent would ask, “What’s the likelihood that another kid is going to have ADHD?” Again, it’s 25% to 50%. There’s definitely a genetic component and a heritable component, but there’s also an important environmental component.

 Do we know of any specific genes that correlate?

 There are a number of genes. There are a number of candidate genes, and that number is anywhere from 5 to 15. What they think is it’s a combination of genes, and each gene has a small contribution. It’s probably 3 or 4 different genes with small contribution, and even with that it doesn’t account for the bulk of ADHD.

Having said that, there are some data that would suggest if you have a certain genetic subtype of ADHD—something that affects, for example, the D4 receptor&mdash;that may be a more persistent form of ADHD. Children who have that may not grow out of their ADHD, as opposed to other kids who don’t have that variant.

 That really speaks to the neurobiology of the disorder, doesn’t it?

 It does, and it is a biological disorder. I think that’s important. Because a lot of people will still say this is just environmental and it’s just excessive stressors on individuals. But in fact, cross-culturally that’s not the case. These genetic studies we’re talking about have also been seen in China. They see them in South America. They see them in Europe. It really attests to the biological underpinning of the disorder.

 Tim, I wonder if you would comment on genetic testing? So much of the population is now involved in, “Let me get some tests so I can see whether I have that.” Can you just make a comment on the test results and the contribution of these different markers?

 Yeah. Someday, genetic testing is going to be prime time. But it’s certainly not there yet. And so all the major professional organizations that work within ADHD advise against genetic testing for ADHD. Organizations, including the FDA, all advise against using that in terms of trying to predict which medication you can respond to.

It also would go, Dave, to the whole issue around neuroimaging. At a group level, if you look at 100, 1000, 10,000 individuals, you’ll see brain differences as a population. But at an individual level, it isn’t discerning enough to say that 

 person has ADHD because they have this brain finding. Again, all the professional organizations advise against using neuroimaging to diagnose ADHD.

Factors That Predispose for ADHD

 I’d really love to bring Andy into the discussion at this point, given your vast clinical and research experience. What effect does ADHD [attention deficit hyperactivity disorder] have on a patient’s quality of life? Because that’s really the bottom line about everything we’re talking about.

 Oh, absolutely. It important that this ultra-neurobiology causes symptoms, but clinically the effect is significantly negative on the patient’s quality of life, for both children and adults. The condition can really have a negative impact on quality of life in virtually all settings, including school, work, a home setting, socially, and psychologically and internally as well.

In school, of course they can get a lot of negative feedback. They may be in trouble all the time. They’re not doing what they’re supposed to do. They can be disruptive. There can be detentions, suspensions, and even ultimately expulsion from school. They don’t do their homework. They don’t do assignments and things they are supposed to do.

At work we know it can be very difficult to meet timelines, to be organized, and to work independently. Judgment is sometimes an issue. Impulsivity.

We also know ADHD can have a significant impact on the quality of life at home. As far as relationships, we know about the stress level it can cause. The negative feedback. The child is always in trouble and needs to be disciplined. The parents are stressed out. “Were we disciplining properly or not?” ADHD can cause problems with sibling relationships and parental relationships, of course.

And then socially, there can be problems with peer interactions and peer relationships. I’ll never forget a mom telling me about her 6-year-old son. “You know, he never gets invited to birthday parties.” And you could tell it was really affecting him. He was starting to notice that he wasn’t getting invited to birthday parties. And so this is a very sad thing.

It can also affect the ability of the family to just go out. I’ll never forget a mom talking to me after successful treatment for her 10-year-old son. She came in, virtually in tears, and I thought, “Oh, gosh, something negative has happened here.” But she told me, “We went to the mall this week and nothing happened.” You’d think it was the most significant achievement in the world, because they just couldn’t take the kid out shopping or to the mall.

Psychologically, it can have a significant impact on the patient’s self-esteem, their sense of self-worth, their identity. They start internalizing very negative self-images. They think of themselves as failures, as dumb, as lazy. “What’s wrong with me?” Really, the impact on quality of life can be quite significant in all spheres of life, and it can affect all relationships that the patient has.

 Well said. I agree with you. Ultimately, we’re not talking about a checklist of symptoms. We’re ultimately talking about functioning, right? How is the person doing in their day-to-day life? And ultimately, to help our patients’ understanding in this diagnostic and treatment process, what we’re really trying to do is assist people to be happier and healthier in their day-to-day living.

 We should highlight that this is all evidence based and research based. Quality of life has been measured in children, adolescents, adults, and even older adults over age 60. So it’s not simply a clinical impression, as your stories clearly reflect, but this is very much research based and shouldn’t be discounted as a clinician’s advocacy.

 Absolutely, David. I’ve worked with many adults. When you make the diagnosis, they look back on the negative problems they’ve had in their lives and there is a grieving process. They feel sad. “You mean this was something I’ve had my whole life, that was treatable, and no one recognized it or helped me with this?”

There is a strong element to psychotherapy, which we’ll talk about later. But for adults, it’s not only the grief of the opportunities lost in the past but the resurrection of self-esteem and self-image and understanding the difference between who they are and what they have, which is ADHD.

 Tim, did you have any additional comments you wanted to make as we wrap up this segment?

 I think what you just heard from everybody is something that’s very important. This is not a cosmetic disorder. For some reason, some people see this as a cosmetic disorder. As Andy and Dave said, this is a very serious disorder that really needs to be properly diagnosed and properly treated.

ADHD: Patient QOL and Misconceptions

 What are the signs and symptoms that would prompt an evaluation for ADHD [attention deficit hyperactivity disorder]? In other words, what brings patients through your door? Andy would you like to lead us off?

 Sure. Of course, it’s very important to evaluate for the symptoms. That’s what we use in our diagnostic checklist, and that’s what we use to establish a diagnosis. But what often brings people in is not the symptoms per se, but the consequences of the symptoms—the negative impact on behavior and on achievement and performance. For instance, children are often brought in because they’re disruptive in school or in class. They can’t sit still. They can’t participate in quiet time or nap time. They may be talking too much.

As they get older, there are more cognitive demands. They get in trouble for not paying attention in class, for not doing homework assignments, and for not being able to work independently. Then, as we get into managing adolescents and adults, there can be significant problems with their organizational skills. Again, meeting deadlines and tasks and doing things they’re supposed to do.

Very often, we see people when they’re in a crisis. It can be that the child either is about to be expelled or has been expelled, or maybe they will be held back a grade in school. Sometimes we’re seeing people when there is a significant crisis going on. For adults, it’s fascinating to me that a lot of times what brings people in are things that we would generally consider positive developments in their life. For instance, they get a promotion, they get married, they have a child, or they are thinking about going back to school. That is a very common scenario that brings people back in. Or they’re studying for an exam or a certification.

Generally, it’s the functional or quality-of-life consequences of the symptoms that seem to bring people in. For instance, a man will come in and say, “My wife is saying if that I don’t get help, she can’t take it anymore and she’s going to leave me.” So I think it’s really important to focus on symptoms but also to look at the functions and the consequences. Because if we fix symptoms but don’t address those very important functional aspects that bring them in, we’re not doing them a service.

 Andy, when patients go to a clinician, they’ll talk about either their distress—“I’m anxious or depressed”&mdash;or their impairments&mdash;“I can’t get my work done, and I can’t be on time.” And so depending on how the patient presents their symptoms, the clinician gets falsely directed to a distraction. Then the patient gets diagnosed with anxiety or depression, or they get diagnosed with some kind of organizational or cognitive impairment. Can you parse out how to direct the primary care physician or the clinician to not focus on the presenting symptoms but go beyond that in regard to the diagnosis?

 Absolutely. You’re bringing up something that is critically important. Sometimes, we do focus on the tip of the iceberg and don’t see the big iceberg underneath the water. A lot of times, when working with primary care doctors, we have to teach them to listen with their inner ear. We teach them to listen for what is underneath the anxiety or depression. What might be causing it? Is this something the patient has been struggling with for a long time? Is it the consequences of these symptoms of ADHD? Unfortunately, what ends up happening is they get treated for depression and anxiety, and then they get referred for treatment-resistant depression or treatment-resistant anxiety. So teaching them about that can also be helpful.

What Prompts Patients to Seek an Evaluation for ADHD

 Let me dig in a little deeper here. Ann, how is ADHD [attention deficit hyperactivity disorder] diagnosed in adults?

 It’s really based on history and symptoms. One of the most important things is to look at their past—look at someone’s childhood. Were they diagnosed before? The problem with that is only about 25% of adults with ADHD who come in for treatment were diagnosed as kids. Their recall of childhood symptoms tends to be unreliable. DSM-5 says you should obtain collateral information.

When folks come in, if they’ve got a mom whom I can connect with, that’s great because moms will remember what was on your report card in the second grade, or if she had to pin a note to your shirt. So getting that information, looking at report cards, that can be really helpful. Talking with a spouse. Because this is based on history, it’s just so important to get that collateral information.

And as David Goodman and Andy Cutler said, it’s important when somebody comes in with depression or anxiety to look at other symptoms. Concentration can be a problem in a mood disorder, an anxiety disorder, post-traumatic stress disorder, a cognitive disorder, and also with ADHD. So it’s really important when somebody comes in to not just go down 1 list of symptoms but really to look at things overall.

We have some good diagnostic scales looking at ADHD. The World Health Organization has the 6-item screener that you can even leave in your waiting room. It takes just a minute or 2 for somebody to complete. You can look at that as part of an evaluation. When you want to go deeper and do a really good evaluation, there is the Adult ADHD Self-Report Scale, which features 18 items they can report on. Then you can do the Adult ADHD Clinical Diagnostic Scale, which goes through a whole list of ADHD symptoms as children and then ADHD symptoms as adults. It takes awhile to do. I’m not very fast at it. It takes an hour and a half or 2 hours for me to do, which may not be practical for folks on the front lines in primary care, where they have only 10 or 15 minutes for a visit. But it’s extremely important to look at.

 You know, I think because of the relatively high prevalence of this condition, it’s very important that we educate and help clinicians think about this and screen for it in addition to all the other things we look at.

 What I’d like to point out here is that for adults with ADHD, we don’t have any specific diagnostic and treatment guidelines from the American Psychiatric Association, which can make this a bit more challenging. For children and adolescents, we do have some diagnostic guidelines, right? In 2000 or 2001, the American Academy of Pediatrics came out with the first diagnostic and treatment guidelines for ADHD in children and adolescents.

Those guidelines were updated in 2011. Then they were updated again in October 2019. The American Academy of Pediatrics is now taking into consideration how common comorbidities are with ADHD. There is a key action statement added to those guidelines about not only looking at the core symptoms of ADHD, but the common coexisting conditions—the comorbidities.

I like to say that ADHD often does not travel alone. It has companions with it. ADHD is often seen with things like anxiety and depression, as Dr Goodman mentioned earlier.

The other guidelines that are new were put out by the Society for Developmental and Behavioral Pediatrics. These guidelines aren’t for diagnosing only ADHD but also complex ADHD. This really followed suit from the American Academy of Pediatrics. Regarding the complex ADHD, it’s important to look again at the comorbidities.

With that, David, what percentage of adults who have a diagnosis of ADHD were actually diagnosed during childhood, for which these guidelines now apply?

 We go back and look at the national comorbidity survey replication study. That was a large US epidemiologic study for adult ADHD, and some very interesting facts came out of that. The prevalence for adults was 4.5%, which translates to about 10 million adults, for which only about 25% are currently being treated. But if we look at the survey data—and this goes back to what was published in 2006&mdash;of the ADHD individuals, 75% were in mental health treatment. But very few, only 25%, were being treated for ADHD. In the total population, only 10% had been treated for ADHD.

And so the idea that you need to have had a diagnosis of ADHD as a child in order to have ADHD as an adult is not well supported by the research. Often, the children are missed, especially if you’re not disruptive. The girls with inattention and the boys with inattention are often not diagnosed until later in life when the impairments begin to occur, when environmental demands start to exceed what they’re required to do.

This idea that you have to listen to the patient is interesting. But I often say that you can’t hear and you don’t see what you don’t know. And so we increasingly try to put ADHD on the radar screen. I know that everyone on this panel, combined, has trained tens of thousands of prescribers, clinicians, and physicians on this. We have to keep reminding our colleagues that this is a highly prevalent disorder in adults.

Accurately Diagnosing ADHD

 We also have to overcome the training deficits. For instance, I don’t know about the rest of you, but when I was trained there was no such thing as adult ADHD [attention deficit hyperactivity disorder]. I still find that there are clinicians out there who either don’t know of such a thing or don’t believe in it. And so we have to overcome that too.

 And to what you’re saying, Dave, about not always recognizing the childhood onset of symptoms, there’s still a bit of controversy on whether there truly is de novo nuanced adult ADHD. This means there is no track from childhood, and it starts in adulthood. I’m interested in what your thoughts are on that.

 Well, it’s interesting because we rely so much on the symptom checklist and not an impairment. If I have a patient who has 4 of 9 inattentive symptoms but they repeated fourth grade, started smoking when they were aged 13, and the parent reports having behavioral problems with them during their adolescence, I might actually treat this person as if they have ADHD.

Very interestingly, I had an adult come to see me, a dad, who reported no symptoms as a child or as an adolescent. At age 15 or 16, all of a sudden his academics started declining. I vacillated whether to treat him. But given his impairment, I gave him medication. Several years later, he brought in his son. Similarly, the son reports no symptoms in adolescence, no symptoms in childhood. He’s now 17 years old and says this has become a problem over the last 2 years. Reluctantly, I treated him, and the outcome was the same. Now, these are exceptional cases.

I agree with Tim that there is a spectrum here. I would caution that if you don’t have the expertise to make these subtle distinctions, the prescription of these medications is problematic. We do know that if you give stimulants to people, their mood, their energy, and their cognition improve. That’s not the basis of a diagnosis for ADHD. Yeah, I see you smiling, so I know you all agree.

 The comorbidities complicate the diagnostic process, don’t they? I think that’s what the American Academy of Pediatrics is getting at with the recent update in the guidelines. Tim, what are some of the comorbidities that can make this tricky?

 Theresa, you bring up a huge point. I would say that a bulk of the diagnostic process and working with ADHD is really teasing out or parsing out what the comorbidity is. It’s estimated that three-quarters of cases have a comorbidity associated with them. We’ve shown in others that this starts very early. If you’re diagnosing preschoolers with ADHD, it starts then and certainly is there through the life span. And the other issue with a comorbidity is it runs both directions.

ADHD puts you at higher risk for the whole sundry of disorders—mood disorders, anxiety, substance-related issues, etc&mdash;and vice versa. If you have 1 of those disorders as a primary disorder, it puts you at a higher risk for also having ADHD. That goes back to what we were talking about earlier: Looking through the symptoms to see what is really going on. One of the more common ones, for example, would be a mood disorder. When you see some frustration, intolerance, a little bit of irritability, that could be ADHD.

But if there is seething anger or if there are severe outbursts, rage attacks, or depression or manic symptoms, that could be either depression or bipolar disorder. Another common overlap with ADHD is anxiety disorders. In fact, this is the one that has the most in common with ADHD, in regard to symptoms. It’s probably the toughest to decide: is this anxiety, ADHD, or ADHD plus anxiety?

Some of that feeling of being on edge during adolescence or as a young adult, is that an internalized hyperactive symptom, or is that anxiety? You often have to track that and better understand the overlap in symptoms there.

Another common one is substance-use disorders. We know in the untreated state for ADHD, about half of adults have a substance-use problem. To reverse it, how many adults with a substance-use disorder have ADHD? It’s between 20% and 25%. So it’s really quite big.

Finally, another one—I don’t know if you want to call it a separate comorbidity or not&mdash;is sleep issues, or sleep disorders. Kids and adults with ADHD often complain of sleep problems and sleep disruption. Most of it is getting to sleep. If you do a polysomnography, you don’t really see huge differences. Yet by report, there are pretty significant differences.

We don’t think sleep is causative for ADHD, but it’s certainly an irritant. If you don’t sleep well, your attention, arousal, and mood is going to be disrupted the next day. Can you imagine that with what we’ve already talked about with ADHD? That creates sort of a worsened ADHD symptomatology as well as functioning the next day.

 Right. It’s absolutely hard to be cognitively sharp the next day if you’re not sleeping. That’s true for both kids and adults. Any other comments before we move on?

 When patients come in with anxiety and/or depressed mood and ADHD, the untrained clinician will say, “Well, your depression is resulting in cognitive changes, and we need to treat the depression.” The ADHD expert will say, “Your depression is secondary to the ADHD and the impairments.” And the expert will say, “I’m not sure whether you have secondary depression to your ADHD or whether you have a primary depression in addition to your ADHD.”

Challenges With Diagnosing ADHD

 This is a great time to move from our discussion on the diagnostic process and comorbidities into the treatment options we have for ADHD [attention deficit hyperactivity disorder]. How about we briefly review the nonpharmacological therapies first in treating ADHD? Other than medications, what options do our patients have, Tim?

 There are a number of options we have, and I would start by saying that it’s debatable if these are the first options. If you’re in the European arena, you might want to start with these first. If you follow guidelines in the United States and Canada, you would think about medicines plus some of the nonpharmacological strategies. Having said that, it appears that structured therapy such as cognitive behavioral therapies are among the most effective treatments for ADHD symptoms. They’ve been studied as both individual therapies but also as group therapies. They have been studied in adolescence and they’ve been studied in adults. It’s been shown that they really do help. Their effect is pretty significant, but these are in partially medicated individuals. There was a recent large multisite study out of Europe that examined which works better: medicines, cognitive behavioral therapy, or a combination?

They found that it was largely the medications, especially if you followed people out to 1 year. It is helpful, and we typically use that in people who have been medicated and are still manifesting symptoms and require additional management.

People have also talked about family-based therapies. There’s not a lot of evidence for family-based therapies for ADHD, although ADHD runs in families and there’s often a lot of chaos and disarray.

Family therapy can be helpful for other reasons: to help the system work better, to help parents engage more with the kids, to help reduce what they used to call emotional instability, and things like that. That could be very helpful in the long term, but isn’t really for core treatment of ADHD.

There is some very exciting recent work for individuals who have a lot of executive function problems. We could argue that’s a comorbidity with ADHD, which certain groups like ours feel is the case. But the bottom line is there’s about a third of people with ADHD who have a lot of problems with organization, time management, hierarchical thinking, and things like that. For them, there is actually organizational training and protocolized versions of how to work with this to demonstrate effectiveness. This is something to think about—that this should be added on. Until this is more widespread, a number of ADHD coaches can help individuals with their executive functions.

Again, time management, organization, and things like that are often occurring with ADHD and may not be particularly responsive to both medication and nonmedication treatments outside that.

Finally, I’d like to just comment on something that a lot of us talk to our patients about. Some people know the data, and some don’t. I’d like to comment on the use of exercise. There’s actually a fair amount of evidence that suggests that exercise is not only for mood and anxiety disorders. For ADHD, exercise also increases frontal lobe blood flow. It actually has what we consider a mild effect—an effect size of about 0.3&mdash;on improving hyperactivity, improving attention. In 1 study in kids, it actually reduced the medication burden. Considering all these nonpharmacological options in addition to other treatments that you’ll hear more about might be thoughtful.

Non-Pharmacological Strategies for ADHD

 What are some of our pharmacological treatment options? Andy, I think you’re doing a paper on the nonstimulants for ADHD [attention deficit hyperactivity disorder] if I remember correctly.

 That’s right. I’m working on a paper summarizing the currently available nonstimulants as well as some in development, and we’ll talk about that later. But as far as currently available nonstimulants, we have only 3 that are FDA approved. Of those, there is only 1 approved for both children and adults, and that’s atomoxetine. Atomoxetine is a norepinephrine reuptake inhibitor. As I’ve already said, it is effective for children and adults.

We also have 2 drugs that are considered alpha-2 agonists. They work by binding to specific norepinephrine and noradrenergic receptors. These are extended-release versions. We have guanfacine [Intuniv], and we have clonidine [Kapvay]. Both of these options are approved only for children and adolescents. But they are approved as monotherapy or to be given in combination with stimulants, which is where I find I get the best results, for a variety of reasons.

Now, there are some treatments that are used off-label. We have antidepressants, such as bupropion. We use SNRIs [selective norepinephrine reuptake inhibitors]. Older tricyclic antidepressants, especially desipramine, also get used. Of course, there are limitations there with efficacy and tolerability.

Even with the 3 FDA-approved treatments, we’ve got issues with inadequate or inconsistent efficacy. Their efficacy is not as strong as the stimulants, and there are some safety and tolerability issues.

A final group of medicines that are used are the wakefulness-promoting agents modafinil or armodafinil. Again, they’re not FDA approved, but there is some evidence that they can be helpful for certain patients. Therefore, they sometimes work their way into our algorithm.

Non-Stimulant Therapy for ADHD

 How about the stimulants? You’ve shared, Andy, the information on the nonstimulants. Ann, would you like to begin talking about the short- and intermediate-acting stimulant medications we have?

 Sure, Theresa. We have methylphenidates and we have amphetamines. They’re old staples. They’ve been on the market for a long time. Amphetamines were first looked at with Benzedrine in the 1930s. And in the methylphenidate class, Ritalin. Immediate-release methylphenidate was first approved by the FDA in 1955.

The methylphenidates come in several different formulations. There is a liquid formulation, there are chewable tablets, and there are tablets that you swallow. They start working pretty quickly. Their onset of effect is between 30 and 45 minutes. Their duration isn’t too long. It’s between 3 and 4 hours, so folks often need to take the medication 2 or 3 times a day. Methylphenidate is approved up to 60 mg by the FDA. That’s really important because when people are getting treated, I often will see somebody who comes in on 5 mg twice a day, or 10 mg twice a day. Those are fine as starting doses, but that’s not enough to get extended efficacy.

As far as other methylphenidates, there’s Focalin. That’s actually a dexmethylphenidate, and it really is intermediate. It’s duration of effect is 4 to 6 hours, and it is approved only up to 20 mg. Normally, folks start with a 2.5-mg dose twice a day and then go up from there.

If you look at the amphetamines, there’s dextroamphetamine. This drug lasts about 3 to 5 hours. It’s approved up to 40 mg for ADHD [attention deficit hyperactivity disorder] and up to 60 mg for narcolepsy. If you look at the package insert, 1 of the things it says is you shouldn’t need more than 40 mg to treat ADHD. It doesn’t necessarily say you can’t go above that.

Dextroamphetamine comes in a number of different tablet sizes—from 2.5-mg tablets all the way up to 30-mg tablets. The generic dextroamphetamine, which isn’t too expensive, is available as 5- and 10-mg doses. Then there is a branded formulation that has a number of different tablet strengths. This option is called Zenzedi. Adderall is more of an intermediate-acting drug. It lasts for about 4 to 6 hours. It is available as 5-mg tablets up to 30-mg tablets. It’s onset of effect really isn’t as quick as with Dexedrine [dextroamphetamine] and immediate-release methylphenidate. It’s probably about an hour, or an hour and a half. Its duration is about 5 to 7 hours. If you look at 1 of the newer ones that is branded, Evekeo [amphetamine sulfate], that is 50/50, regarding d- [dextroamphetamine] and l-amphetamine [levoamphetamine]. Adderall is 3 to 1, in regard to d- [dextroamphetamine] and l-amphetamine [levoamphetamine]. Evekeo has an onset somewhere between 30 and 45 minutes. In a classroom trial that I was the lead investigator on, we were able to squeeze about 10 hours out of it. That is when everybody is dose optimized and, in the best of all situations, compared with placebo. But if you look at things in general, it’s probably more like 5 or 6 hours that folks are going to get out of it. You can dose it once or twice a day. And you can start at 5 mg and go all the way up to 40 mg. You can increase all these medications on a weekly basis. You don’t have to start low and go slow. You can start low and ramp things up pretty quickly. It’s really important to do that to get the best therapeutic effect.

 You know, Ann, I’m surprised by how commonly the immediate-release preparations are still used today. I know not just for augmentation, sometimes we’ll use them to extend the duration. But there are a lot of people who are just managed on immediate-release preparations.

 That’s true. I’m sure Tim wants to bang his head on the wall when he hears that, looking at substance abuse.

Short- and Intermediate-Acting Stimulants for ADHD

 Thanks, Ann, for your nice summary on the short- and intermediate-acting stimulant medications that we have available. There has really been an incredible change over the years, since I started in this field 20 years ago. We have so many more options.

David, how about the long-acting stimulant preparations? What else is out there?

Well, talking about options, at last count there were 28 different preparations of stimulants available. And so this becomes a very confusing quagmire for clinicians to sort out which medication they should use. So let me sort this out.

There are 28 different preparations, which breaks down into 4 chemical compounds. You have methylphenidate and dexmethylphenidate, which are 2. And amphetamine, which is racemic or a dextroamphetamine. Or you have Adderall, which is mixed salts—4 salts. We think about compounds first and then think about delivery systems.

For each of these compounds, there’s a different delivery system that will extend the duration of action. The technologies you use are various. How do you sort through which medicine you use? It’s generally recommended to start with a long-acting option, whether you want to start with a long-acting methylphenidate or a long-acting amphetamine.

I don’t know, from a patient’s profile, who is going to respond better to 1 versus the other. Based on Dr Sam Cortese’s meta-analysis of 144 studies, research would seem to suggest that an amphetamine is preferential to a methylphenidate. Methylphenidates, however, may be a bit more tolerable in children compared with amphetamines. That’s group data. On an individual patient basis, I have no way of knowing who is going to respond. So the technologies are important because they give you different delivery systems and different durations of action.

They also give you a different PK [pharmacokinetic] curve. And so the duration is based on the PK curve and the delivery system. If you choose a beaded preparation of mixed amphetamine salt XR [extended release], that’s going to give you a different duration and a different PK profile than an amphetamine that’s a pro drug and not a mechanized delivery system. For clinicians, think about compound first. If the patient responds to a compound but has adverse effects, you may want to change that delivery system.

If they don’t respond to the compound, you may want to change the compound and then take a look at the delivery systems. This is very much based on clinical impression. I know Tim can speak to a lot of the research that will help differentiate this, but at the end of the day, the clinician is really left with a lot of choices. That’s great. But the more choices there are, the more confusion that occurs. We want clinicians to choose 2 or 3 options that they’re comfortable with, so that they don’t get overwhelmed and then decide it’s too complicated to treat. So Tim, I wonder if you could just elaborate on the research basis of that?

 Well, you know, there is now more and more research about how quickly the PK curve changes and how people respond to that, and also the dissolution curves. There’s certainly work that shows that, for example, not all extended releases are exactly the same, and they have different profiles. The analog classroom model that Ann and others have been involved in have actually helped ferret that out—important differences.

Another thing I would say that helps differentiate some of the extended release, at least in kids, is there are certain kids who can’t take a pill. But they can take beads.

They might be able to take a medicine like Adderall XR, for example, where they can open it up. Or Vyvanse, where they can open it up and spread it and take it that way. Some kids can’t even do that. Some need a solution or suspension, for which case they may have to use 1 of the suspension forms of the medication. I think that’s another important differentiation regarding the different extended-release compounds.

It’s very interesting that you mentioned that, because in adults there are varying sensitivities. This idea that there’s weight-based dosing in adults is simply not a good way to follow this. I have patients who use low doses and have great responses. I also have patients who are on extremely high doses, and that’s what they need. I know in children you have guidelines for that, but I’ve heard you say that they are guidelines and really should not be the absolute dictation.

 They are guidelines. A lot of people use up to 2 mg/kg per day of a methylphenidate in a kid, and up to 1 or 1.5 mg of amphetamine. But you’re right. For those people who are on higher doses that are way over FDA-approved doses or if you’re nervous about the dose, you can get levels. You can get levels of amphetamines, and you can get levels of methylphenidates.

Our guidance is to get them at peak. And again they’re optional. These are guidelines. Like Dave said, there is no 1-fits-all approach.

Long-Acting Stimulants for ADHD

Just to move the discussion along, I think there is a point that might be confusing right now to listeners. We’re meshing together some mechanism-of-action pieces here with delivery systems. Those are really 2 different categories of topics, right? When we talk about, for example, short-acting stimulants and intermediate-acting stimulants and long-acting stimulants, what changes there?

It’s the delivery system, right? We’re delivering the medication over longer periods of time, when you talk about a long-acting medication by changing, maybe, the coding. Or in the case of something like Mydayis, you’re adding a third bead to that delivery system to make that drug last longer. Mydayis has been shown in studies to be a 16-hour medication. This is probably the longest-acting stimulant that we have in terms of our PK [pharmacokinetic] data.

Then there’s mechanism of action, which is a separate category when you compare something like Intuniv [guanfacine], a nonstimulant that binds to the alpha-2A adrenergic receptor, to a medication that is a stimulant medication either acting as a reuptake inhibitor or enhancing release of norepinephrine and methylphenidate. It is important to distinguish between those 2 things.

I wanted to mention 1 of medications that sometimes takes a little while to explain to clinicians and patients alike, and that’s Vyvanse [lisdexamfetamine]. Vyvanse is the only prodrug stimulant formulation we have available. And as a prodrug, it’s actually an inert substance. In its parent molecule form, Vyvanse actually is not an active amphetamine. It’s not until it’s broken down and acted upon by an enzyme in the body that it splits that molecule for the parent molecule to then release dextroamphetamine. It becomes amphetamine in the body, but in its parent molecule Vyvanse is actually an inert substance.

What does that mean in terms of patient care? Well, patients will often describe that it feels different. It doesn’t feel like that kick, the way some stimulants can feel to them. And they appreciate that they can’t exactly tell you when it starts and stops working. Physiologically, it feels a little more subtle to patients. This is not true in everyone, but that’s an example where when you carefully look at both delivery systems and mechanisms of action, how that translates to mean something to patients.

That’s a very important point. To go back to the long-acting stimulants, it’s important for clinicians to know, as Tim [Wilens] mentioned, that there are a variety of preparations. You have long-acting liquids. You have long-acting pills. You have long-acting patches. You have chewables. The way in which you take the medicine is determined by the technology that’s used in that medicine.

And you can move back and forth between a mechanized delivery system, like a mixed amphetamine salt XR, or you can go to a prodrug like Vyvanse and have different delivery systems and different PK curves. The subtleties are distinguishable by the patients. Often, when I try to get them to be on a drug, I say, “Is there anything you don’t like about this?” And their answer is, “No.”

Prodrug Therapy for ADHD

 Tim, what does all this mean, in terms of discussing the efficacy and safety of each of these classes of medications, taking into consideration the short-acting and long-acting stimulants and the nonstimulants?

 I have to say that many of the people on this panel today have been the ones who have been very involved in study these medications in different models. But across the board, the stimulant medications are highly effective for the treatment of ADHD [attention deficit hyperactivity disorder]. They’re among the most powerful, or I should say most effective, agents that we have of all the psychiatric medications we use. In general, three-quarters of people respond to stimulant therapies. Peoples’ typical responses in terms of how much you drive down their symptoms range from 30% to 50%.

If you want to use a fancy term, they call it 

. The effect size is roughly 1.0, which is a massive effect size. And this has been demonstrated in what we called naturalistic studies. These are studies in the home. People are at home, and they do standard trials. Again, look at the panelists who have been very involved in these analog classrooms, in these laboratory classrooms, using these exquisitely sensitive systems to monitor every movement of a child and map it out against their blood levels and things like that.

It’s demonstrated to be effective within a half an hour out to 14 to 16 hours depending on the class of medication. I’m actually really impressed with the long-term data too, though. We’ve always said that people say, “One of the shortcomings with the data is that there’s no long-term data.” That’s not true. That’s simply not true. We just published something that looked at this, and there are a host of long-term outcomes data.

If you look at these mega studies, these big registry studies where they can map out treatments over time—looking at who got their medications when, use between kids to those people who are on versus off medications at different times&mdash;they’ve demonstrated a number of things. They show long-term reductions in substance-use disorders. They show long-term reductions in criminality, motor vehicle accidents, traumatic brain injuries, and general injuries. They show reductions in mood disorders and reductions in suicidal behaviors.

It’s really great, from a long-term-outcomes standpoint, to say many of the things we talked about earlier—about these severe impairments and consequences of untreated ADHD&mdash;are being reversed with ongoing treatment. The vast majority of that treatment in these trials are with the stimulant medications.

Treatments for ADHD: Efficacy and Safety Data

 I want to home in on something you just said about substance abuse and ADHD [attention-deficit/hyperactivity disorder]. What does that mean for a prescriber who's initiating, potentially, a stimulant medication? What are your thoughts? What's the feedback on that, Tim, regarding the safety of stimulants?

 We know there is a percentage of individuals who misuse and divert their stimulants. Typically, the diverted samples are to college students. But we know of some take-home messages that can really help us out. Number 1, we know there is a difference regarding immediate-release stimulants, and misuse and diversion. The extended-release stimulants are better than immediate-release stimulants. And that's something we can do right away to help reduce the amount of misuse and diversion out there.

Another thing we know is that we need better stimulants. We need short-acting stimulants that can't be ground up and snorted and things like that.

Another thing practitioners can do is educate the person sitting across from you, who may be an adolescent or young adult, and say, “Look, it's not OK to sell your medicine. It's not OK to give it away. That has ethical and legal connotations if you do it. And by the way, when you store it, don't put it in a medicine cabinet. That's where people look for drugs. Put it in a chest of drawers. Keep it safely stored away.”

And finally, the other thing that data help us, as prescribers, understand is we don't need to be sending kids to school with 270 or 360 pills. We don't need these huge reservoirs, because that's where a lot of the diversion is occurring.

Now with e-prescribing, you can prescribe much easier. So I think there are some things you can do to help mitigate some of the abuse liability concerns we have with stimulants and still treat individuals who are in this age group with the most effective agents we have available.

 I strongly agree with what you're saying. My experience with patient care is that safety starts before you even write that first prescription for a controlled substance. It's all about the relationship and the collaborative discussion at the beginning. It's really a verbal contract between the patient and prescriber, isn't it? They're trusting that I'm going to do what I need to do to safely monitor their prescriptions. And that includes things like checking blood pressure and heart rate, and making sure I'm seeing them in follow-up appointments. And in kids, checking height and weight. It also means that they're part of that equation. The patient needs to be responsible about agreeing to attend their follow-up appointments, and agreeing to potentially having random toxicology screens done. They need to agree that they are to be responsible with where they store that medication. And if it happens to disappear, as in it is stolen, lost, etc, it will not be filled early, for their safety. It's an agreement we have before the first prescription is even written.

There are those logistics around managing the stimulant medications. And then, also, thinking about mechanism of action, delivery system, and trying to match what's the best fit for that patient. Some of the medications are going to feel differently to an individual. Vyvanse had those likeability studies done. It was given to a drug abuse population, and they were asked how much they liked that drug. It didn't score very well. I think part of that is because it is a longer-acting preparation, as you've discussed, Tim. The longer-acting preparations tend to be diverted less. So those are some things to think about when you're choosing a therapy, before, again, you even write that first stimulant prescription

Substance Abuse and ADHD

 While all of this is self-evident, it puzzles me and everyone in this field that 55% of all stimulant medications are short-acting, and 65% of all prescriptions for stimulants written in the United States are written by primary care physicians. How is it that this message simply doesn't seem to take hold in the prescription practices of many of the physicians seeing individuals with ADHD [attention-deficit/hyperactivity disorder]?

 Is there an evidence-based recommendation for hierarchy in choosing medications to treat ADHD? What can we recommend to our viewers?

 I suppose we'd have to rely on European guidelines. We don't have guidelines in the United States. I'm part of a working team that's developing these, but we're several years off in accumulating all of the research. The European guidelines, the Canadian guidelines, there are international guidelines that we can recite.

But again, despite reciting these guidelines and lecturing tens of thousands if not hundreds of thousands of prescribers, we still see the perpetuation of immediate-release stimulants. I know it may not be the wish of the clinician to prescribe this way. The incentives both economically and from insurance prior authorizations become major obstacles, and in my opinion, contribute to the ongoing perpetuation of the short-acting stimulant prescriptions being written.

 Ann, did you want to weigh in on the question of the evidence-based recommendation hierarchy for choosing medications?

 Sure. If you want to look at adults, the recommendations are to start with an amphetamine. Amphetamines work better than anything else. They work a bit better than methylphenidate. There was a big meta-analysis that looked at more than 50 studies, more than 8000 adults, and what they saw was the effectiveness of amphetamines compared to placebo was highest. Methylphenidate was next, while atomoxetine was lower on the totem pole.

And when they looked at head-to-head comparisons, amphetamines were more effective than modafinil. Then, atomoxetine and methylphenidate. And regarding tolerability, interestingly, modafinil, amphetamine, methylphenidate, and atomoxetine were less well tolerated than placebo. That makes sense, right? Placebo shouldn’t have a lot of adverse effects, although I have had patients who have experienced horrendous adverse events with placebo.

And later, when we unblinded our studies, we found they were on placebo. There were only a few studies that compared dextroamphetamine with other amphetamines, but it's a little better tolerated than other amphetamines. So looking at all outcomes, amphetamines are the first-line choice for adults with ADHD. And I think that prescribing data bear that out in the United States.

 I appreciate that. But also, as a clinician, I think the differences are nuanced. I think there is enough information on that, and it's really a choice of which one you want to use. Kind of what you were saying about the adverse effects, there may be an advantage in efficacy with amphetamine, or an advantage with methylphenidate for adverse effects and tolerability. And when you look at it in the end, it's pretty similar.

 Yes. Tim, you and I started to discuss the safe use of the stimulant medications. Did you have any comments, in terms of adverse effects and helping patients and clinicians? What is it you're watching for?

 Theresa, you were mentioning that when you were talking about the contract, part of their contract is, “You're going to be monitored.” And that's actually important. In general, the stimulants have similar class effects. They can reduce your appetite, and they typically do that during the day. In the shorter term, you often will see weight reductions. And even longer term, you'll see continued weight reductions in those people chronically treated with stimulants.

Probably the more controversy comes around height. Is there really a height difference? I think most people would agree if you look at the literature that out 2 to 3 years there may actually be a mild reduction in height velocity. You don't shrink. Rather, you don't grow as fast. But if you look at that beyond 4, or 5, or 6 years, you lose that, there is some type of attenuation with that.

Having said that, you really do want to maintain height and weight examination of kids every 6 months to a year to see how they're doing. You want to keep an eye on those kids who really just stop growing.

In addition to that, Theresa, as you mentioned, you check blood pressure. There could be an increase in heart rate and blood pressure in individuals. Having said that, if you look at studies that were conducted by the FDA and AHRQ [the Agency for Healthcare Research and Quality] that were published in 2011, actually now almost a decade ago, in the best journals, they didn't really show any cardiovascular adverse events associated with stimulant medications over the long term. I think that is really important to know. They didn't show any in kids, and they didn't show any in adults. And in fact, if you saw anything, you saw a slight protective effect. Again, I'm not sure I buy that, but it was positive in terms of not showing real problems.

And finally, mental status issues. There are going to be kids who get more irritable on stimulants. Again, there are slight differences. Maybe a little bit more mood lability is found with the use of amphetamines over methylphenidates. But in the end, I think you're watching for that with all of them.

You can also see sleep issues. Again, as we said earlier, you can see these pre-existing. So it may be that they had a sleep disorder and you're only asking about it when they're being treated. And there, it pops up, but it actually was pre-existing.

The same with mood. It may be that they have a mood disorder and that got unleashed. Or, it actually was there before and you only saw it because you were now asking more systematically when people are on the medications. Those seemed to be the most important. There have really been no long-term effects seen. What you see short term is what you're seeing long term. You're not seeing ominous outcomes long term with these medications.

Adult ADHD Treatment Recommendations

 David, when do you switch between drugs of the same class, such as switch from a methylphenidate to another methylphenidate, versus switch from one class to another class of medications, such as switch from a methylphenidate to an amphetamine?

This is a very important question for clinicians. When patients don't respond or start having adverse effects, and they say, “Look, I don't really want to continue taking this medicine,” what is the clinician to do? If you have 28 different stimulant preparations, how do you decide, besides throwing a dart at a dartboard? Well, let me give you some parameters for that. For me, if the patient gets better on the compound—let's say they're on a methylphenidate and their symptoms get better, their daily improvement is better&mdash;then I'll stay with the same compound.

But if they say they have adverse effects on that compound, then I'm going to look at the technology, the delivery of mechanism into the system. And to sort that out, I'm going to then assess whether those adverse effects occur an hour or 2 after they take the medicine, or 6 hours, where there is a plateau, or whether it's occurring 8 to 10 hours later, when it's wearing off. Depending on when the adverse effect is occurring in the time frame of the duration, then I will alter the technology that I choose—the delivery system.

Let's say the patient is on a beaded preparation, like amphetamine mixed salts XR [extended-release], and their drop off effect is too fast. They get irritable. They get lethargic. They get moody. So now I want to extend the duration. I'm probably going to change to a different duration of action. I'm going to change to a triple beaded option, or I may use lisdexamfetamine as a prodrug that has a different delivery system. To back up, if the patient gets better on a compound but they have adverse effects, then take a look at the timing of the [adverse] effects. See if you can then change your technology within the same compound. If the patient doesn't respond to a compound, then I'll change to a different compound.

I don't go from methylphenidate to dexmethylphenidate. Rather, I'll go from a methylphenidate to a dexamphetamine, or vice versa. I think this is an effective way of sorting it out for clinicians, thinking through the algorithm of choosing, preferably, a long-acting stimulant medication.

Often, what clinicians will do is they'll start with a long-acting medication, titrate it up, and the patient will say, “It's wearing off at 3 o’clock or 4 o'clock.” Then they give the patient an immediate-release booster to get them another 4 or 5 hours. I've been an advocate of not doing that. If you increase the milligrams of the long-acting in the morning, you will extend the duration out. For example, clinically, if using lisdexamfetamine, if I go up 10 mg, I'll get another 2 hours of duration. If I go up 10 mg on mixed amphetamine salt XR, I'll get another 2 hours duration. So if you know that, I would increase the morning dose of the long-acting to increase the duration. Unfortunately, sometimes when you do that the adverse effects will occur on part of the PK [pharmacokinetic] profile. And that's the dose at which the patient can't tolerate the drug. That's the way to think through, do I go from compound to compound, or do I stay within the compound category and change the delivery system for duration of action?

 Thanks for sharing your thought process on that, David. Anyone else have a different approach they might use?

Regarding the addition or supplement of using immediate-release with extended-release, I'm probably a little bit more liberal than Dave, I also use it in individuals during the afternoon when they sometimes have to work longer. Sometimes they don't, but that allows them the option to do that.

The other thing I wanted to comment on, to what Dave was saying, is that when you're going within or between different preparations, I think it's important also to remember, are you talking about a racemic mixture or are you talking about am isomeric mixture? If you're moving from dl-methylphenidate to d-methylphenidate, you're going to do that often because you have some efficacy, need a little bit more efficacy, and want to get better adverse effects.

And the same goes with amphetamine. Regarding amphetamine, I think people forget that many of the compounds, such as if you're using the mixed amphetamine salts—Adderall, Adderall XR&mdash;that's going to be a D, L preparation. It's not going to be the racemic. It's going to be mixed.

If you go to d-amphetamine, as you were hearing—let's say with Vyvanse or some of the other ones, like Evekeo that have more of a D to L&mdash;you're really moving more to the isomeric preparation. That will buy you a bit more efficacy with fewer adverse effects. I think that also becomes sort of nuanced.

Switching Medication for ADHD

Andy, help us out. Discuss the efficacy of multimodal treatment options for ADHD [attention-deficit/hyperactivity disorder] in adults.

 I think in any field of medicine we know that we give a multimodal treatment plan. For instance, if you're treating diabetes, you don't just give insulin. You talk about dietary and lifestyle interventions. I think the same would be true here. The problem is that our nonpharmacologic treatments haven't demonstrated as much efficacy on their own as they have in combination with the medications, or compared to the medications alone.

That being said, there are some things that are reasonable. I think part of the issue is that it is very hard for a person with ADHD, for instance, to participate in therapy or other kinds of nonpharmacologic strategies because of the problems with attention and organization and stick-to-itiveness.

However, that being said, again, the combination of medication with various modalities is very reasonable. That would include things like ADHD coaching and organizational techniques. I find, for instance, that people do very well with various digital devices. The advent of smartphones has been tremendously helpful for a lot of people.

There is also very good evidence on sleep hygiene and ADHD. We know that there is a higher incidence of sleep abnormalities in patients with ADHD, and medication could contribute to that. So sleep hygiene is critical. We know if you're sleep deprived, you will have problems with attention and executive function and cognition, and mood and energy.

We also know that diet can be very important. The brain needs energy and fuel. It needs healthy energy and fuel. Certainly, feeding it refined sugar and chemicals is intuitively not helpful.

There is evidence of exercise and ADHD, as Dr Wilens mentioned earlier. This is something I recommend all the time. You don't have to be like Arnold Schwarzenegger and go to the gym and pound heavy weights. You can simply do things like go out for walks, walk your dog, or get on an exercise machine while you're watching TV so you're not even aware you're exercising. All of these things are reasonable.

Another area that's really exciting is the idea of digital therapies, or digital interventions. Some of these can be digital forms of cognitive behavioral therapy, but some of these can be things like a therapeutic video game, or what's called BCI [brain-computer interface]. One was recently released into the market. There's another one in development that could be on the market very soon. These are some of the multimodal treatments that can go into augmenting the medication treatment that we’re going to use. I find patients like having these kinds of options. They feel more of a sense of engagement and control over their treatment. I’m sure Dr Wilens has a little more information about some of the data on these interventions.

 I don't think there's an adult that I see who doesn’t need some additional assistance. If we've treated them medication-wise, they need something else. And really, the data show us that if you look at medicines versus therapies, over the long haul, and our European colleagues have helped us realize this, medicines are really fundamental. The medicines are the foundation to which you add the cognitive behavioral therapy, and probably not the opposite.

It's probably not sufficient to do cognitive behavioral therapy without any other treatment and expect to get as good of an effect, particularly if you're following these patients over the long term. I think the data do help drive us in that direction. I also think that you raise the whole issue of, we don't have the solution at this point. So we're trying this, we're trying that, and we're trying that in addition. I think you have to be creative, as a treater, pick 4 or 5 things, many of the things that Andy just laid out for you, that will be helpful for these adults.

 I highly agree with you. I completely agree with you.

In terms of multimodal treatments, are there any medications that have been studied and FDA approved? Are there any medication combinations that have been studied and FDA approved, to be used safely and shown to have efficacy, in combination?

 This is a good point. We do this all the time. The fact is that the alpha-2 agonist extended-release guanfacine and extended-release clonidine now have now a very good database and are actually FDA approved for use in combination with stimulants. What's nice about them is they smooth out some of the effects. With stimulants, you have a certain duration of time before they start working after you take them. And then, of course, they have a certain duration of effect and then wear off. They have to, or you wouldn't go to sleep at night. And so, there are times in the morning or in the evening when the stimulus is not necessarily effective. And theoretically, adding these medications can cover those times.

Also, they have synergistic and complementary mechanisms of action. And also, one of the most unusual things I've seen in my almost 30 years of clinical research, in psychopharmacology, is that adding these 2 medications together actually decreases the adverse effect profile. It's as if there is a little bit of complementarity not only in efficacy but also in tolerability.

Multimodal Treatment of ADHD

 Let's look toward emerging treatments and future directions. It's always exciting to think about this topic. Andy, I know you've had a lot of involvement in the recent development of the serotonin norepinephrine modulating agent, SPN-812 [viloxazine hydrochloride]. Can you tell us a little bit about it?

 Yes, I'd be happy to. SPN-812 is an extended-release version of a medication called viloxazine. Historically, viloxazine was approved overseas, in Europe, as an antidepressant agent. It was available for many years. It was found to be effective for depression, and was very safe and well tolerated. The problem was it was an immediate-release, short-acting preparation.

And so, a company called Supernus [Pharmaceuticals, Inc] has developed an extended-release preparation. It has been studied fairly extensively in children and adolescents. They've had positive data, and they submitted it last November to the FDA for consideration for approval for the treatment of ADHD [attention-deficit/hyperactivity disorder] in children and adolescents.

What is unique about it is its mechanism of action, which you alluded to; the drug is a serotonin norepinephrine modulating agent. It binds to certain serotonin receptors, and it has some moderate activity as a norepinephrine reuptake inhibitor. And what this combination has been shown to do in animal models is increase the release of serotonin, norepinephrine, and importantly, dopamine, in the prefrontal cortex, which is the part of the brain that we believe is critically affected by ADHD.

As I mentioned, these trials were positive studies at various doses in children and adolescents. Besides mechanism of action and efficacy, one of its advantages is this is a capsule with beads. We talked about a lot of stimulants that are formulated this way. You can open the capsule and sprinkle the beads on certain types of foods.

There is no available nonstimulant preparation that you can use for people who either can't or won't swallow pills. So this would certainly be a very important addition to our options. As I mentioned earlier when talking about other nonstimulants, they tend to be limited by inconsistent or inadequate efficacy, and there are some tolerability issues and some safety warnings.

It appears that you have efficacy with SPN-812, although it's certainly not as efficacious as the stimulants. We know that's a difficult bar to reach. But it also appears to have a somewhat unique tolerability and safety profile. Also, because we know it was effective and approved for treating depression, and the mechanism of action also predicts that it might be effective for anxiety, I'm excited about the possibility that this could treat 2 of the more common comorbidities with ADHD in children and adults, and that is depression and anxiety.

 What caught my attention was even having the word serotonin listed when we're discussing ADHD, right? Usually, we think about dopamine, norepinephrine. And so, I'm really excited to hear more about this. Is there anything you want to add that is of most interest to you with this particular compound?

Treatment Landscape for the Management of ADHD

EP 1: Clinical Subtypes of ADHD

EP 2: Factors That Predispose for ADHD

EP 3: ADHD: Patient QOL and Misconceptions

EP 4: What Prompts Patients to Seek an Evaluation for ADHD

EP 5: Accurately Diagnosing ADHD

EP 6: Challenges With Diagnosing ADHD

EP 7: Non-Pharmacological Strategies for ADHD

EP 8: Non-Stimulant Therapy for ADHD

EP 9: Short- and Intermediate-Acting Stimulants for ADHD

EP 10: Long-Acting Stimulants for ADHD

EP 11: Prodrug Therapy for ADHD

EP 12: Treatments for ADHD: Efficacy and Safety Data

EP 13: Substance Abuse and ADHD

EP 14: Adult ADHD Treatment Recommendations

EP 15: Switching Medication for ADHD

EP 16: Multimodal Treatment of ADHD

EP 17: Novel Nonstimulant Therapy for ADHD

EP 18: Exciting Therapies Under Investigation for ADHD

EP 19: Treating ADHD: Current Unmet Needs

EP 20: Managing ADHD During COVID-19

EP 21: Evolution of Therapy and Destigmatizing ADHD