Timothy Wilens, MD

Timothy Wilens, MD, talks about the presentation of the APSARD 2021 conference on ADAIR Pharmacokinetics and Pharmacodynamic Data. More on the presentation can be found 

is chief of the Division of Child and Adolescent Psychiatry and is co-director of the Center for Addiction Medicine at Massachusetts General Hospital.

Videos

What observations are being noted in the field with new agents for the treatment of ADHD?

New Deterrent Stimulants for ADHD

Key opinion leaders close the discussion by considering developing medications for pediatrics with ADHD.

 Ann, as a researcher, you’ve been doing a lot research on new medicines or new formulations that work. Could you summarize, from a hope perspective, what’s on the landscape in the pipeline for ADHD [attention deficit hyperactivity disorder] meds?

 If you’re looking at immediate release, there are 2 amphetamine products. One will probably be approved next month. Not with the labeling that we had hoped for with this manipulation-resistant technology, but it’s basically Evekeo [amphetamine sulfate]: manipulation-resistant pellets in a capsule that you can’t snort very well. Whatever household tools you need—apparently, they had to go through a whole bunch of them, and it’s hard to smash it up and get the drug out. There is also 1 that’s AR19, an Arbor [Pharmaceuticals, LLC] drug. The other is called Advair [fluticasone propionate, salmeterol]. It’s further behind in the pipeline, but it has this manipulation-resistant property and has done well in studies where they’re snorting and trying to liquefy it to use it IV [intravenously].

Another drug that’s going to be approved in March is KP415, and it has a component of a prodrug to serdexmethylphenidate—that’s a lot to say. It’s a prodrug of dexmethylphenidate, but it also has an immediate-release component so it starts working within 30 minutes. We did studies with it, and it still had some effect at 13 hours. The prodrug part has less abuse liability in the studies that they’ve done, but it’s got that immediate-release component. I’m not sure exactly where that’s going to end up.

They do have KP484, which is just the serdexmethylphenidate, which doesn’t have the immediate-release component. Hopefully it will wind up with some labeling that encourages people to use it and insurance companies to pay for it.

There are a couple of nonstimulants. I alluded to viloxazine, although I didn’t say its name. It was the 1 that was an antidepressant in Europe for many years. It will probably be approved in about 2 weeks. Viloxazine will be the first nonstimulant that’s come out in quite a while. It’s a serotonin norepinephrine modulating agent. It doesn’t work with the dopamine, but other than atomoxetine, it works a little on serotonin. Maybe that’s what’s helping with the depression with its antidepressant effects.

There is 1 more that’s a little further behind, centanafadine. It’s a triple reuptake inhibitor that’s going to hit dopamine, norepinephrine, and serotonin. It has been shown in phase 2 studies, in a whole bunch of adults, to beat placebo. The biggest problem I see with it is the fact that it’s a twice-a-day medicine. Anything you have to take twice a day is a nonstarter right out of the gate. We’re all encouraging them to do the work to turn it into an extended-release drug that people have to take only once a day.

I did a review paper. There are about 40 drugs in the pipeline in various places, but the ones I talked about are the ones we’ll probably see in the next year or 2.

That’s really exciting just to hear that we have new potential alternatives with nonstimulants, and they’re not just me-too stimulants anymore. They are trying to make them safer. As Bob [Findling] said, you’ve got to get the medicine into people and find the best and safest way to do it.

I have to say that first, this has been an extraordinary discussion. I certainly hope you found this to be valuable to your clinical practice and learned a lot about ADHD academically. I want to thank our panelists for their views. I also want to thank all of you for watching this 


-Dr. Findling receives or has received research support, acted as a consultant and/or has received honoraria from Acadia, Adamas, Aevi, Afecta, Akili, Alkermes, Allergan, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Arbor, Axsome, Daiichi-Sankyo, Emelex, Gedeon Richter, Genentech, Idorsia, Intra-Cellular Therapies, Kempharm, Luminopia, Lundbeck, MedAvante-ProPhase, Merck, MJH Life Sciences,NIH, Neurim, Otsuka, PaxMedica, PCORI, Pfizer, Physicians Postgraduate Press, Q BioMed, Receptor Life Sciences, Roche, Sage, Signant Health, Sunovion, Supernus Pharmaceuticals, Syneos, Syneurx, Takeda, Teva, Tris, and Validus.

-Dr Gephart is retired from the practice of medicine. He is on the faculty of the 

 for a course entitled “Patient Centered Mental Health in Primary Care.” He receives a stipend for serving as a virtual consultant to Course graduates who call in and present difficult cases. He has no other financial contracts to report.

-Dr Childress reports receipt of research or writing support, participation on advisory boards, and service as a consultant or speaker for Adlon Therapeutics, Aevi Genomic Medicine, Akili Interactive, Allergan, Arbor Pharmaceuticals, Cingulate Therapeutics, Emalex Biosciences, Ironshore Pharmaceuticals, Jazz Pharmaceuticals, KemPharm, Lundbeck, Neos Therapeutics, Neurovance, NLS Pharma, Otsuka, Pearson, Pfizer, Purdue Pharma, Rhodes Pharmaceuticals, Sunovion, Supernus Pharmaceuticals, Takeda, and Tris Pharma.

-Dr Wolraich is professor emeritus from the University of Oklahoma Health Sciences Center. He is on the steering committee and a faculty member of the REACH Institute, a non-profit organization providing CME training on mental health to primary care physicians. He has no affiliations or investments where he receives any compensation, and he is no longer in any clinical practice.

-Dr Wilens is Chief, Division of Child and Adolescent Psychiatry and Co-Director of the Center for Addiction Medicine at Massachusetts General Hospital. He receives or has received grant support from NIH(NIDA). He is or has been a consultant for Arbor, Otsuka, Ironshore, KemPharm and Vallon. He is the author of 

Straight Talk About Psychiatric Medications for Kids

Massachusetts General Hospital Comprehensive Clinical Psychiatry 

Massachusetts General Hospital Psychopharmacology and Neurotherapeutics

 (Elsevier). He is co-owner of a copyrighted diagnostic questionnaire (Before School Functioning Questionnaire) and has a licensing agreement with Ironshore (BSFQ Questionnaire).  He serves as a clinical consultant to the US National Football League (ERM Associates), U.S. Minor/Major League Baseball; Gavin Foundation and Bay Cove Human Services.

The Future of the ADHD Treatment Landscape

A discussion on the widespread abuse of stimulants amongst pediatrics with ADHD (attention deficit hyperactivity disorder), with special consideration to ongoing substance abuse liability trials.

Ann, when we first started talking about the unmet needs, 1 of the first things you commented on was to come up with a medicine for ADHD [attention deficit hyperactivity disorder] that doesn’t have the abuse liability, that doesn’t have that abuse potential. If I went across and polled everybody on the panel, people would say that that is a concern, either their own concern or a concern for their patients who they sit across from.

It does beget the whole issue about the stimulants and abuse liability. In fact, the only black box that stimulants have is concerns about addiction, and it’s a big black box right there in the package insert, and there are some real concerns.

When you talk about nonmedical use of stimulants, you’re either using them if you’re prescribed, not using them appropriately, or you don’t have a prescription and you’re using them. We know overall that about 10% of high school kids and older adults have experimented with stimulants or other prescription pain medications. Stimulants are now No. 1. It used to be opioids, but it just shifted. Up to about a third of college students have used stimulants nonmedically. That’s a big number. It aggregates in college students, that’s the group who do it the most. If you look at similarly aged individuals and vocations, as Harlan was just talking about, or in the military, that’s not the issue.

We also know that those who use stimulants nonmedically have high rates of ADHD. Not all of them have ADHD, and they have more neuropsychological dysfunction and high rates of substance abuse. Where do they get it? They get it from friends and family, and they get it from reservoirs of pills.

The other disturbing fact that’s emerged—and this has been seen in multiple studies—is that it turns out that about 40% of stimulant misuse is intranasal, which is a huge concern. There’s an NIH [National Institutes of Health] study on this. We’ve studied a lot around nonmedical use of stimulants, and I’ve also collaborated with Sean McCabe [of the University of Michigan School of Nursing] and Ty Schepis [of Texas State University], and they do a lot of work in this area. I saw Mark flinch there because you don’t expect it to be that high. It’s a much smaller percentage of intravenous. Why is that important? Because Stephen Faraone and I just published a paper looking at poison control data. We found that if you use intranasal or intravenously, you have 20-fold likelihood that you’re going to have some serious medical morbidity or even death, and that is 1 of the things we worry about with intranasal misuse of these compounds. That is occurring in up to 40% of kids using stimulants nonmedically.

I’d be interested in having the panel talk about the different trial designs being used for abuse liability. Some of them are using people who are what we call connoisseurs of stimulants, who have experience with that. Some are in normal controls.

Ann, do you want to us give a sense? You’ve been involved with or looked at some of the abuse liability trial designs that are ongoing.

 There are several drugs too. Just last week the FDA had an advisory board looking at what they’re going to do with these medications that people are developing. Really, we can’t call them abuse deterrent, because people could still misuse them, but they’re manipulation-resistant formulations.

I was disappointed, somewhat exasperated, at the end of the meeting because the advisers didn’t see what a big deal all this was. There’s a lot of education not only of physicians and patients and families, but we have to educate our friends in the government in so many areas.

Mark, what patients are you worried about as a pediatrician? What have you taught your residents? What do you teach other pediatricians? When you were practicing, what do you worry about? What patient populations do you focus on when you’re thinking about the abuse liability?

 When there is substance abuse in the family or some history of it. The other thing I do is with the kids who have done well on stimulants and are planning to go off to college. We talk about taking their senior year, when their grades aren’t as important, and trying 1 of the nonstimulants to see if they can get as good benefit. Because if they’re going to college out of state, they’re going to have to get another physician to take care of them. Also, if they’re caught giving the medication to their friends, they can get into trouble for dispensing controlled substances. I try to, where possible, see if there’s an alternative when they’re in college, and that’s worked for some. Also, educating them that it is an addictive drug and that they need to be careful.

Bob, are there prevention strategies or groups you worry about or things you talk to parents or groups about to potentially obviate this from happening?

 Certainly Mark has talked a lot about patients you need to worry about or family members you need to worry about. But at the end of the day, what is also important is that you’ve got to take the medicine as prescribed. That means you’ve got to make sure the medicine goes where it’s supposed to, to whom it’s supposed to. I always love the, “Well, they’re old enough to do this, so I just left the pills out on the counter.” I hear that all the time. You’re all shaking your heads, but tell me who hasn’t heard that repeatedly. Then you have to remind the parents and not just take it out and leave it on the counter or put it next to the toothbrush.

Remember, the hard part is having many of these parents—who themselves may struggle with being unorganized—do it so they can remember and make sure the youngster does it. Because of this abuse about concern, you could stockpile stuff not even intentionally. Then all of a sudden, look what you got here: a medicine that could be really quite detrimental in multiple ways. Own the medicine. The medicine must go to the right place, at the right time, into the right person.

 You don’t find out until they get caught. I’m careful: I do all the things that you all talk about. I tell people not to give it to their friends; it’s a felony. A few months ago, I had a young man who wound up in the emergency department. He was taking fluoxetine, which I prescribed. And I’m like, “He has ADHD but didn’t want to take medicine for it.” He just turned 18. I’m like, “How can that give you dystonia? How can the fluoxetine do that?” I’m looking it up, but I didn’t see it. I come to find out—he finally fessed up—that he had gotten into his little brother’s IR [immediate release] methylphenidate. He had crushed it up and snorted it, and sure enough it gave him a dystonia. This was a 5-mg tablet. A lot of our patients out there, I am sorry to say, are doing things they shouldn’t be doing, even though we’re educating them and we don’t know until they get caught.

 That’s an important point. If I could summarize what I heard, because this is a lot of wisdom that people just got. We’re talking about when you’re talking to parents of kids growing up and that age that Ann was talking about, everybody from young to old. You’re talking about misuse and the importance, as Mark was saying, of knowing that these can be abused. Take them as prescribed, as Bob said. Encourage the supervision of adolescents who are taking these medicines. I would also add safe storage if you’re talking to college students. Don’t keep your controlled substances in medicine cabinets. That’s where people look.

The other thing I would add to it is—and we’ll hear more about the new meds— extended release, when you have high-risk situations. Use the extended release, and we’ll talk more about the immediate release, some potentially new versions of immediate release that don’t have quite the abuse liability. at least from the intranasal perspective.

Then, as Bob was saying, monitor your pill counts. Get the pill counts right. Don’t give people a reservoir of pills. Don’t write for 120 when 30 is what they really need, especially because you can do e-prescriptions now, so write size it so you don’t have reservoirs from which people can sell or give their medication.

Stimulant Abuse in Pediatric ADHD Populations

Experts in the management of ADHD (attention deficit hyperactivity disorder) consider various unmet needs in the treatment of pediatric patients.

COVID-19 [coronavirus disease 2019] hopefully will end one of these days, and what will persist is ADHD [attention-deficit/hyperactivity disorder]. It does bring up some of the things that we’ve talked about with COVID-19 and highlights some of the issues we’re dealing with medicines and shortages. There is a lot of need still yet to be unveiled in ADHD in terms of treating it.

Ann, you’ve been at the forefront of a lot of clinical research in this area, you know what the needs are. Can you give us a lay of the land of what you think are some of the major areas where we need to do better?

 If we could come up with a medication that worked as well as a stimulant and had low abuse potential and didn’t affect growth, we’d have a home run. I don’t see anything like that in the pipeline.

How about some other things? What other needs do you think about? Should whatever we have treat comorbidities?

 It would be nice, because as we talked about, I do clinical trials, and I’m trying to find kids with just ADHD, and that’s only about 25% of the kids out there. It would be nice if we can have a medication that will help with ADHD and may treat some of the mood and some of the anxiety symptoms that are comorbid. There is something coming that was used as an antidepressant for about 3 decades in Europe, that also is effective in ADHD. It’s a nonstimulant, it doesn’t work as well as the stimulants do, but doesn’t have that abuse potential. It hasn’t been studied with comorbidity here yet, but I have hope. I have hope for it, since it was used as an antidepressant.

What’s your sense about through the day coverage? Where do you think we are now, and where do we need to go?

 Some of the medications, for example, extended-release guanfacine and atomoxetine, we know do help with some of those bookend times.. The kids have so much trouble before they get off to school in the morning, and then the medication lasts into the evening. None of the stimulants have 24-hour coverage, and I don’t know that we would want a stimulant that had 24-hour coverage, because I don’t know what it means when we’re blocking dopamine 24 hours a day. There probably needs to be some downtime with that.

Harlan, you’ve thought a lot about this. Your book and everything about what works and what’s not working in ADHD. What are some of the things that you also see from a pediatric standpoint that we need to do better?

 I’d like to get away from the medicine thing. I don’t disagree with any of that. Schools are not properly, what should I say, they’re not user-friendly for kids with ADHD, and there’s very little that’s been done. The best you get is just sit near the teacher, or that sort of thing. Moving into middle school and high school, class sizes are huge, 30, 40 kids in a class. There’s very little time to do homework in the class; the teacher barely can collect yesterday’s homework and explain tomorrow’s, and then they’re out the door. The kids come home with 2 or 3 hours of homework, which is just killing for a kid with ADHD.

I remember 60 years ago being in high school, and homework was like an hour a night. Of course, I didn’t have a learning problem, but it was not a big chore. We’ve just got to do something different. Sitting in a row of kids drives a kid with ADHD crazy. The whole school system, I think, needs to change. That’s one thing I wrote down. We’ve got to do better about vocational counseling. I tell parents all the time, “Your kid’s smart enough to be a doctor, but he wants to be a plumber, so for goodness sake, let him be a plumber. Don’t get hung up there.” I see every once in a while an ex-doctor who now works finally as a plumber, or something like that.

 One of the big issues is communication between all the players. It is not yet a good system. There are some out there that work well but are not supported enough to do, where the information from the school, to and from, can be in the process, the better communication with parents, and as we talked about with the telemedicine. Communication between the pediatricians and the child psychiatrists, the communication between the pediatricians and if there’s a therapist or a psychiatrist, are really not there. And there are a lot of barriers there for protection of health information, but they decrease the communication.

In the case conference calls we have, the pediatricians…still have relatively little contact, either if the child has a therapist, or if they’ve sent them to a child psychiatrist for help.

Unmet Needs in Pediatric ADHD Management

A discussion on the altered dosing of medicine for pediatrics with ADHD (attention deficit hyperactivity disorder) during the COVID-19 pandemic.

One of the questions that does come up, and Harlan you may want to lead this one, is are people stopping their medication? Do you advise people to stop their medication because they’re not in school? Do they need their medication? Are you increasing their medication? What’s medicine management during this period?

It’s all secondhand because I don’t see patients anymore, but there’s a lot of variability out there. For years I’ve always preached don’t stop taking the medication on the weekends for example, or during the summer, because a lot of people think medications are just for school. That’s something we’ve been trying to get people to do for years. Now, what I hear is there’s a lot of difficulty….

 No, difficulty being consistent with taking the medication. There’s a lot of inconsistency. As you know, there was research that you did years ago that if you didn’t take medication on Saturday and Sunday, it took you to about Tuesday to get back up to blood level again where you were working OK. Monday is usually a very important day in school, so you weren’t adequately medicated Monday morning when the teacher was presenting a new math process or something. That’s just accentuated that. I think medications are not being used.

The other component of that Harlan, about the medication, is that, I would agree in our area, variable. More people are using more of them, and I think one of the byproducts, because parents are seeing their kids and realizing how bad the deficits are, plus these kids are already being super-challenged by being on Zoom all day. Our adults without ADHD [attention-deficit/hyperactivity disorder] are challenged. Can you imagine kids with ADHD?

To top that off, we just recently had a symposium about drug shortages at the American Academy of Child & Adolescent Psychiatry meetings in 2020. One of things we were talking about is that there’s just-in-time invoicing, where people don’t have a lot of surplus of medicines available in the distribution lines right now. This is all being strained because of COVID-19 [coronavirus disease 2019], and pharmacies are being challenged with increased orders in some areas that they haven’t seen previously. So we’re dealing with quotas and distribution problems.

People are having more problems finding, in particular, stimulants…and the specific ones they may want, and they may have to go to 3 or 4 different pharmacies with every different prescription they get to find it, and that just makes it harder. That’s just another barrier to filling prescriptions. It seems like Ann, you’re seeing the same things in Las Vegas?

 Yes, and we have the highest unemployment rate in the nation right now. I think we’re down to 12.5%, so a lot of people have lost their health insurance. The casinos really did a good job and they tried to carry them through most of the summer, but a lot of people have been laid off. That means they can’t afford the brand name medications that they were getting. I’m having to do things that I don’t like to do, and that’s switch people to immediate-release [formulation] that they can afford. That’s a problem. Probably the only good thing for COVID-19 with me is I bit the bullet and got up and running on e-prescribing. But then, if they have to go to 3 or 4 different pharmacies to get it, and pharmacies won’t tell you if they have it or not because they don’t want you to break in and steal it. Then I have to send it to this pharmacy, and then go back and send it to another pharmacy, and I don’t know if everybody else has had that problem. It takes up a lot of time just to try to get somebody their medicine.

 I haven’t been as strict about taking it 7 days a week, and it’s from the perspective of knowing that on average, the kids stay on it about 3 years despite what you recommend. And you have to have buy-in from the parents and the children for the medications, and I’ll go with what they see as what’s working for them. There are kids who have fewer demands on the weekend, and the parents don’t like their appetite suppression, or they don’t like some things about them. So, I’ll go along with whatever I can get them to buy into to be on the medications.

 One of the fallouts from COVID-19 that we might want to talk about, Tim, is increase in adolescent suicide attempts.

Yes. You’re right that there are increases in drug use disorders, there are increases in depression, remembering that 20% to 30% of kids with ADHD have depression, so that’s a major risk in ADHD. What you said Harlan is correct, that we’re already stepping into an endemic of increased suicides in kids, and this is going to be amplified by COVID-19. Have we seen that yet? No, but it’s too myopic, it’s occurring, but your point is well taken.

Medicine Management During COVID-19 Pandemic

Key opinion leaders provide caregivers with practical advice on how to effectively manage pediatrics with ADHD (attention deficit hyperactivity disorder) during the COVID-19 pandemic, with special consideration to various educational difficulties.

Thinking about the family in these settings, often, no surprise to anybody on this, this is a highly genetic disorder. And often there’s a parent who had ADHD [attention-deficit/hyperactivity disorder] who’s trying to care for kids at home with ADHD, and that can create a tremendous amount of stress. Ann, what kinds of things do you recommend to families in terms of resiliency and managing right now?

 One of the things, if people have some financial stability, if they have some extra money, there are a lot of substitute teachers right now who are unemployed. Some of the families are getting together and creating these learning pods. They will have a teacher who was a substitute, a real teacher because they’re used to dealing with kids, and they’ve had background checks, so that makes them ideal, for $15 an hour. And 2 or 3 families will get together with maybe 4 or 5 kids, and they’ll go from house to house, or a couple of days at one house, a couple of days at another house. They’re in a room with their computers or their iPads, and basically they have a teacher who is making sure everybody is getting on the right website at the right time. That’s great if families have the money.

I have another family, the mom has 3 children, she’s a kindergarten teacher, so she’s working too during the day. She bought Echo Dots, and she programmed them with alarms for when the kids are supposed to go to the next class, and she’s got the websites up on the computer where her 7-year-old can just click to this, and click to that. Alexa has been helpful for some of our families in doing this.

It’s interesting because for the last 15 years when families would say, “I want to homeschool Johnny,” I would say, “Do you know what that involves? You are going to become a full-time teacher.” And I’d do everything I can to try to get them to not homeschool, and now we’ve just got to deal with it with everybody.

That’s a great point, and the other thing I would add is, what we’re trying to do in our area is build kids’ resiliency right now, and their parents’. There are components of resiliency, and it helps these kids with ADHD because most of these kids have a lot of emotional anxiety, as well as mood dysregulation. We teach them components of mindfulness meditation mixed with coping skills. What do you do if you’re feeling anxious? What do you do if you’re feeling moody? How do you manage feeling lonely when you miss your friends? What are some techniques you can learn?

There are resiliency groups online, there are several apps that you can get, at least for the mindfulness meditation part, and some of them are free. I encourage people to recommend that or to advocate to have a resiliency group, a virtual group, started in your area because these can be very helpful for these kids, like I said, many with ADHD in particular, where they have other conditions, other things going on, that make them vulnerable.

 I’m probably the only one in the group here who’s seeing people in the office now. I get lonely. I don’t want to do just telemedicine, and I do like to get vital signs; I get blood pressure and weight. We have Buddy, the therapy dog, and initially I was saying just the parent and the child who has the appointment come in, because we were all afraid of COVID-19 [coronavirus disease 2019], which I think we should be. But everybody’s got their mask on, and I’ve got my bleach bottles, and if brothers and sisters want to come in, fine. It’s their 1 outing for the month that they come and see Dr Childress, and even the snarky teenagers are happy to see me these days, which is great for my self-esteem. Of course, we have the therapy dog, Buddy. A lot of people come to see Buddy, I realize it’s not me. That’s OK.