508- Combination Therapy: Medication Strategies for Hard-to-Treat Complex ADHD

Speaker A
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Speaker C
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Carol Fleck
Welcome to the Attention Deficit Disorder Expert podcast series by Attitude magazine.

Hello, everyone. I'm Carol Fleck, and on behalf of the attitude team, I'm pleased to welcome you to today's ADHD experts presentation titled Combination Therapy Medication Strategies for hard to treat complex ADHD. Leading today's presentation is Doctor Timothy Willans. Doctor Willans is chief of child and adolescent psychiatry and co director of the center for Addiction Medicine at Massachusetts General Hospital. He's also a professor of psychiatry at Harvard Medical School.

Doctor Willin specializes in the diagnosis and treatment of ADHD, substance use disorders, and bipolar disorder. In today's webinar, we'll discuss complex ADHD. That's when a person with ADHD has one or more coexisting conditions, and we'll learn about the medications used to treat these diagnoses. As many of you know, ADHD rarely travels alone. Depression, anxiety, mood disorders, and autism are often comorbid with ADHD.

In today's webinar, doctor Willans will explain the common conditions and symptoms that can accompany ADHD, and he'll tell us about medication strategies to guide patients and their providers. Finally, the sponsor of this webinar is play attention. Empower yourself by developing strong executive function and self regulation. Cognitive control is your superpower. Play attention can help you develop it.

Backed by research from Tufts University School of Medicine, play attention empowers individuals to prove attention, emotional regulation, and overall performance. Its NASA inspired technology ensures tailored support for every aspect of life. Click the link on screen to take play attentions ADHD test or schedule a consultation to start your journey toward improved executive function and emotional regulation. Call 828-676-2240 or visit playattention.com to learn more. Attitude thanks our sponsors for supporting our webinars.

Sponsorship has no influence on speaker selection or webinar content, so without further ado, I'm so pleased to welcome doctor Timothy Willans. Thank you so much for joining us today and for leading this discussion. Well, thank you very much. And I really appreciate attitude taking on issues that are a little bit more, excuse me, a little bit more difficult and challenging. And these are the group of individuals that I've worked with my entire life and have dedicated my professional career to both studying in terms of new treatments, but also clinical care.

Speaker A
And I want to welcome everybody from a very beautiful Boston, Massachusetts. So we're going to be talking about complex ADHD, and I'm going to add a little bit to this in terms of talking a little bit about refractory ADHD. Also, I'd like to start with my disclosures, and I do work with a company that's in this area and have confidentiality disclosures with others. Most of my disclosure is about my clinical work, where I do work with psychopharmacology, and I also work with addictions. And there may be some questions about that at the end when it comes to comorbidities.

So in terms of sort of an overview to ADHD, I know most of you know this, most of you can give this part of the lecture, but I just want to remind everybody that it's considered, you know, within six to 9%. A very recent publication came out to slightly higher, but, you know, roughly six to 9% of the population and about four to 5% of adults. The former figure was more for kids and adolescents, and the four to 5% is adults. About 50% of individuals who are children today will continue to have adult ADHD into adulthood. If you're starting with an adolescent, a 16 or so year old, how many of them will continue to have it into adulthood?

At least three quarters. And then there's arguments about how I define it and this and that. Generally, that's what you can expect. We're going to be addressing this. It's associated with high degrees of psychiatric comorbidity, co occurring problems like you have ADHD and depression, or ADHD and bipolar, or ADHD and anxiety.

It's associated with impairment. The reason we're talking is because this is not just a cosmetic disorder. I don't need to be telling you about that. If you're living with a loved one with ADHD, it causes a lot of impairment, it causes struggling and it causes suffering. And those are the three major benchmarks to when do I think, as a psychiatrist, I need to treat somebody pharmacologically or with some type of a psychotherapy?

So I'm going to jump right into starting with the various medications that we have, and remind everybody that we have actually a growing portfolio of medications that are available, such as we have the stimulant medications that are FDA approved. We have atomoxetine. And I'm going to go back and forth between brand and generic names, because sometimes people don't know that that's strattera. We have elf agonists which are FDA approved things such as Guan fasting extended release, also called intuitive clonidine extended release, which is referred to as Caphae, although there's a new one. Oneida is new.

We're just commenting about it. That's a new FDA approved, long acting clonidine. And then you can use clonidine extended release or guan fasting extended release with stimulant medicine. So the combination is actually also approved, and we're using that combination. And that is going to be one of the things we're using for refractory cases or cases of comorbidity.

So what else do we have? We have loxazine XR, which is also just recently available. More recently, it's Calbrey, and that's a non stimulant that works. And I'm going to be walking through the various treatments we have. So let's start with the stimulant medications, and let's start discussing things such as methylphenidate.

Now, this is a relatively complete, there's always name shifts or whatever, but this gives you what is available with methylphenidate preparations to help treat individuals with ADHD. I'm starting with the assumption that sometimes people aren't better with their adhd because they're just, they still have core symptoms, they have comorbidity, we'll talk about, but they still have some core issues with the disorder. And when you're thinking about that, that you're still having active symptoms. One of the considerations with stimulant class medicines is to go up on the dose. There is a very robust literature that shows as you go up on the dose, typically you get better response for your adhd.

Low doses work, moderate doses typically work better than low doses, and higher doses work better than lower moderate doses. Now, in some individuals, as you go up on the dose, they actually get worse. You can't just ramp up doses rapidly. You always want to bring up the dose slowly. But it helps to understand that we have a number of methylphenidate different preparations, 15 different preparations that I recently looked at the literature, and that seems to be what we have.

The doses that we often go to, especially with methylphenidate class agents, is higher than the FDA approved dose only because not as much methylphenidate as you give gets into the system. As you may imagine, only about 20% of what you actually ingest actually gets into the system. And because of that, because of wide differences, how much gets into the system, it may be that some people require higher doses and conversely, some lower. The other thing we think of is we recognize that there's different types of methylphenidate agents. In other words, there's long acting, short acting, intermediate acting.

The short acting ones may be more appropriate in children. So, for example, Ritalin, Ir, folklin, those are considered shorter acting, and they last for so hours. For preschoolers, those may be helpful for adding on to an extended release preparation that will cover ADHD later. And that's often a problem then. Another clinical pearl is individuals who have a lot of mood dysregulation, moodiness with stimulants, especially an extended release.

Let's say you're using an extended release stimulant, consider using a short act, and we sometimes find that that works so much better. The other reason I highlight the various preparations of methylphenidated. So you have duration differences, but also how you administer. You can give them, like most people, like a tablet, you can have capsules that you open and spill, and that can help certain kids who have problems, you know, taking oral pills. You have liquid suspensions that can help kids who have problems taking pills.

It also is great because you can go milligram to milligram, and you can get just the exact dose using that. We have patch technology where you actually wear a patch for people who don't want to take oral things or people who may have GI issues. We have ones that you take in the morning, and then we have ones that you take at night, a stimulant that releases the next day and helps and works really well. If you have kids who have a lot of morning disruption, let's say so it's great to have a whole variety. And that's just for methylphenidate.

To remind you, we also have amphetamine class agents. We have ten of these. Still a lot. These are very similar in terms of different long action, short action, intermediate action. Adderall dexadrine tablets tend to be on the shorter side, and then you've got things such as dexadrine spatials that are more intermediate.

And then we have extended release, like Adderall XR Vyvanse, which, by the way, is generic. Now and then you've got these long, long ones, like midas, which is a very long preparation lasting to 16 hours. And again, they have suspensions, they have patches of this so that you can really give it in any different version of preparation, which is often part of the problem. For, quote, refractory or non responsive ADHD, there's many things you can do to get around so that you can still use stimulants. Now, this is a little bit complicated.

I'll just walk you through. This is really a chart that looks at switching from initial stimulant. And this is more focused on adults. But what it basically says is that people who don't respond to methylphenidate class agents should be tried on amphenib because you're going to, in many cases, get people doing better and they like to switch. And the same individuals who start with amphetamine preparations and for whatever reason have side effects or don't have a good response should be tried on methylphenidate preparation.

So we frequently shift class from this one from methylphenidate to amphetamine or amphetamine to methylphenidate. In general, if you look at guidelines plus clinical practice, typically kids are started on methylphenidate class agents. And then if they've tried different ones and not to satisfaction, there's refractory cases, they'll move to the opposite, to an extended release form and then onto a amphetamine class agent. In contrast, adults are often started on amphetamine class agents first, and then we'll move to methylphenidate. If there's usually untoward side effects or the tolerability is not very good before we exit.

Again, a big reason that people stop medicines is because of side effects. And as part of complex adhd, it's comorbidity, but it's also being able to use stimulants because they're so effective. And you need to monitor if they have cardiac issues, such as chest pain, chest discomfort, shortness of breath, you're going to have to stop it, and you're going to want to go to a primary care doctor or cardiologist to be sure that there's not underlying issues. If there's insomnia problem sleeping, has this always been there and it's just gotten worse, or is this like new and really worse? Sleep hygiene is really important.

Getting to bed at the same time, waking up at the same time. You can't tell people when they go to sleep, but you can wake them up not playing video games too late. Not doing exercise too late, not drinking caffeine too late. Watch afternoon or late doses of medicines. What other medicines?

We use melatonin. Melatonin has been shown to be effective both short and long term. We use clonidine, one of the treatments of ADHD can really help with sleep. Sometimes we use tricyclic antidepressants. Those also are effective for ADHD, but sometimes at low doses.

Those are great sleepers and they help treat the ADHD at night and through the morning, and then mirtazapine, which is an antidepressant in adults, but has been used for sleep for many years. Using it at a low dose, low dose seems to be best. Dental issues people who are grinding wear guards. One thing to realize as you get older, teenagers, young adults, dry mouth is one of the most common side effects. So be careful and use, you know, good dental hygiene, keeping your mouth wet, not eating sugared candies, because sugared candies on top of a dry mouth, that will create dental caries very quickly.

Finally, with mood and irritability, which is a comorbid condition, evaluate what is happening. If it's at the peak, like two to 3 hours after, you're going to have to have to try a different preparation totally, because that's indicating that. Is it occurring during wear off? Well, you can try microdosing stimulants later. You can try omega three fatty acids, good old omega three s.

They work. The other thing is, if it's a comorbidity that you're seeing unveil itself, then you're going to think about treating mood. So you may have somebody in therapy, or you may think about shifting to a different preparation of a medicine, or treating the mood with a medicine and treating the ADHD. Let's move on to other things we're using. And veloxazine is interesting.

It's a non stimulant, it's a noradonergic agent. It's approved across the lifespan. The dosing is 200 in kids, 400 in adolescents and up to 600 in adults. And I go up by 100 milligrams a day. I'm not in any big hurry on that.

The side effects, it's generally well tolerated, but it can cause somnolence in some cases, and sometimes just the opposite. Sometimes a decreased appetite, like a stimulant, and sometimes headaches. That's been shown across the lifespan in terms of dosing. Like I said, I usually start it for a lot of people haven't used this yet. Start it relatively slow at 100 milligrams and go up 100 milligrams a week.

I don't bump into as many side effects and sometimes I get a really good response at a lower dose because I'm not going too quickly. A couple of things to know. We are thinking about using this for individuals who have mood in addition to ADHD. It's an antidepressant in Europe for years. We're thinking more and more that this may be a really interesting agent for mood and ADHD.

In fact, my understanding is that companies doing a study right now to look at that, and I have experienced that like mood dysregulation with ADHD, this irritability, real frustration that is really hard on both parents and the kid or the individual if you're older, that sometimes gets better with just using voloxazine. A couple things about things to know. It is a strong inhibitor of one of what we call an isoenzyme in the liver. And because of that, the one a two. You have to be a little bit careful.

If you're using certain things like other psychiatric medicines like duloxetine, there's other ones to be concerned about. So just anybody on it should take a look at that. The other thing company indicated to me is be careful about caffeine because it may accentuate caffeine. In other words, you have your Starbucks in the morning and it's like having two. So be careful about caffeine.

Also, I want to note that there's some medicines that care a lot about if you start them earlier, and one of those medicines is adamoxetine strattera. In other words, it doesn't work as well as if you've started a stimulant, then adamoxetine, as opposed to most non stimulants, don't care if you've been on another medication first. Why is that important? Because if we're talking about adamoxetine, we're really talking about use of the medication often for ADHD plus anxiety. So, comorbidity with anxiety, think atamoxetine.

It's a very good medicine for ADHD and anxiety. There have been studies in children, adolescents and adults that show improvement in the ADHD and anxiety. In fact, it works as well as many of our medicines we use for anxiety, such as what we classes of medicines called the serotonin reuptake inhibitors. The SSri's works just as well. It's also helpful for tick disorders and maybe for disruptive disorders.

Another one that we often use atomoxetine for is ADHD. Plus substance use disorders. We're not going to spend a lot of time talking about substance use today. But if you have that and you say, I want to use a non stimulant, many of substance users also have anxiety as a problem, also in addition to their ADHD, and it will help the anxiety, the ADHD, and it will reduce episodes of, let's say, heavy drinking or heavy smoking for those individuals. So adamoxetine is a good one to know about.

Doesn't have a lot of drug, drug interactions that's been studied in substance users, for example. Another thing to think about that often people ask me about is what do we do in older, like adolescents, young adults. And one of the things you can do is add guan fasting to extended release. People are using that already. It's a very common medicine.

But what you may not know is you can go to higher dose. There was a study that we published a few years ago, a multi site, large study, and we dosed it up to seven milligrams a day in adolescents. The highest dose typically was roughly around six. Most people didn't need the seven or didn't want to go to seven. And basically it worked quite well in terms of treating ADHD.

It was effective, no surprise. And I've used that in my practice a lot, up to six milligrams a day. I have a number of adolescents and adults who were responding, but their response wasn't as good, so we just increased the dose. So again, data to support that we really need new phones. T Mobile will cover the cost of.

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Speaker C
Ctmobile.com dot so let's talk a little. Bit about some of the psychiatric comorbidity that people have. And I'm going to start with a little bit of a case. A seven year old with ADHD, plus excessive difficulties with organization, time management, thinking sequentially, shifting what they're working on, and stopping. And when we think about that, we think about it in terms of ADHD and executive functioning and what a lot of people say, what is that?

Speaker A
Cognitive executive functioning. I call it the willin'sism. Is the secretary of the brain kind of helping you. You do this, you organize. Organization is the symptom that really taps into it.

But time management, initiation, shifting, stopping, that's all under that rubric. And some kids and adults, a quarter of those with ADHD, don't do as well with that. These kids have more problems with disruptive behavior, more anxiety, depression, social functioning problems. It really causes a lot of issues. What can you do about that?

Well, we just published a paper, and there's multiple positive treatments for executive functioning and ADHD. So you can do physiologic, you can get out, and you can do jumping jacks every day. So exercise helps, but on the day you do it, and it doesn't have to be a lot, but that has a big impact on it. There are treatments like cognitive behavioral therapy and organizational training that have been shown to be effective. There are neurologic things like neurofeedback and stuff, not so helpful.

I wouldn't do that. We did not recommend that in our paper. And then there's digital, there's some online gamification things, you know, cogmed. There's other ones that are available that had some impact, some effect. Problems we have with some of the available digital ones is some of them are very expensive, and some of the ones that we reported on are not available.

And finally, there's pharmacologic, and I'm going to talk about that in a second. So one of the things we found is, first of all, stimulants can help, but they often are not sufficient to manage all these executive functioning. We're starting to see that some of the non stimulants, like strattera, atomoxetine, calbri, or veloxazine seem to help. And then when you mix non stimulants, like I just commented, with stimulants, you can get impact. In fact, if you look at adamoxetine, strattera and stimulants, there have been a number of studies, and we did a big study of this.

And basically what this, an analysis of all the studies done, the what ten studies showed that the available evidence suggests, but does not confirm, that this drug combination, that is adamoxetine plus a stimulant, methylfenadine or amphetamine, may benefit some, but not all, patients who have tried several ADHD medicines without success. So it is something to think about just add a non stimulant with a stimulant, and that may be helpful. What else has been tested? As I was indicating, you can use an extended release form of a alpha agonist, like guadalfasting extended release, or clonidine extended release plus a stimulant. Those are FDA approved.

They improve ADHD. And there was a small study from UCLA that showed that it actually also improves executive functioning. Secretary of the brain organization, time management, etcetera. So one of the ways to manage what I think of as a cognitive comorbidity of executive function and in ADHD, then you can think about using two medicine combinations if necessary. Another thing we're using is a medicine that's used for Alzheimer's called memantine.

And there have been studies that have looked and focused on executive functioning. Looking at it, you know, there's different ways to measure it, but finding, if you look at it clinically, using clinical scales, that you see some improvement. And I found it with memantine. So memantine is another one, dosing five to ten milligrams twice a day. They have an extended release also.

That works. And it may also be helpful for social cognition, the capacity to read verbal cues for kids who have ADHD, plus some autism or autism spectrum.

The other thing that works in this realm, even though I'm focusing on pharmacotherapy, like I was commenting, is for residual symptoms of ADHD and executive functioning. Thinking about psychological treatments like cognitive behavioral therapy and organizational training, those are sort of the two big areas. Not my group, but another group at mass general has a guide on this, for example. And they've published data showing significant improvements in kids who are treated with cognitive behavioral therapy. These are largely medicated kids, so it's not verse medicine.

Medicated kids who are still struggling, which is a very common scenario with executive functioning. And what they found is that it works. So this is what they focused on, is organization and planning, how to deal with distractibility, how to reset things if you start to get off of things, and how to deal with procrastination. So you think about it. Organization, planning, procrastination, those are all what we call executive function.

And the response rates for individuals by self report or parent report were between 50% to 60%. So pretty good outcomes for kids who had stable medicine regimens, but still had a lot of cognitive executive functioning. But let's move on. What about the tough thing about autism spectrum disorder? We know that if you look at samples of ADHD, if you look at rates of ADHD, in community samples of kids with autism, it's anywhere between 20% to 30%, and it goes up to 50% if you look at clinical samples.

So lots of autism in individuals with ADHD. I apologize if you're hearing sirens. It's usually not that I am in a general hospital, so there are sirens and not much we can do about that. But sorry, it seems like they keep coming by. We recently reviewed the literature on autism and ADHD treatment.

How do you treat autism plus ADHD? And you probably know that in the older versions of our diagnostic statistic manual, you couldn't have both disorders. You could just have prominent hyperactivity. But now you can't have autism and ADHD. Because of that, there's increased diagnoses.

A couple of things we've learned is, first of all, there was a large study done a number of years ago called the Rupp research units in pediatric psychophysiology, pharmacology, and they studied treatment of ADHD. They didn't look at ADHD per se. They looked at hyperactivity, because at the time, that's what they could do. And what they found was improvements in ADHD symptoms, the hyperactivity, but the response rate was closer to 50%, not the regular 70% to 80% we see in neurotypically developing kids. So signal number one was it didn't work as well in these kids, kids with more significant autism.

Number two, they had more side effects, so it didn't work as well, and they had more side effects. The good news is it seemed to help something called self affect regulation, losing it. Kids tended to lose it less when they were treated.

So studies like that and a whole host of other studies that we reviewed showed that ADHD can be diagnosed in autism spectrum and should pharmacotherapy is effective. But one thing we've learned is if you have what we consider intellectually capable patients with autism spectrum and ADHD, the response rate to using non stimulants and stimulants is pretty much the same. If you have lower functioning autism spectrum, be careful with both stimulants and non stimulants. And both of what I'm talking about refers to both stimulant and non stimulant class medicines, mainly methylphenidate, mainly adamoxetine, a little bit less with clonidine, didn't work quite as well. But the other non stimulants and the stimulants, same, too.

If you're working with lower functioning autism spectrum or a lot more autism traits in ADHD, careful. A. Your effectiveness is not going to be quite as good as it is with kids who don't have autism spectrum and ADHD. You'll have more side effects, dysregulation, appetite issues, sleep issues. Pretty much everything goes from here up.

It just becomes more significant. And consider different preparations. You may have to get more fancy about what you're using. For example, sometimes tablets work great and you can grind the tablet. Sometimes the kids won't deal with tablets.

You have capsules that you can open to sprinkle on food, and that works okay. They have dissolved tables that you can dissolve in your mouth. They have suspensions pretty much for stimulants and non stimulants now, and they have patch technology. So think about what is the best way to work, because these kids often bring a whole set of other issues with them. Now, I want to shift a little bit.

Let's look at this case, which is an eight year old presenting with ADHD and excessive worry somatization, thinking a lot about physical things, stomach aches, headaches and things like that. Always feeling on edge, worries about what others are thinking and has sort of isolated anger that's kind of related to the above. So what do we think about that individual? Well, we would say that they have. They probably have anxiety disorders along with ADHD.

Anxiety is one of the most common co occurring issues with ADHD. It is absolutely very common. And in fact, it can sometimes be hard to know, does somebody have ADHD or anxiety or both when they both co present? Because they both start early in life, they both have a lot of overlap symptoms and both cause quite a bit of impairment. If you've decided and figured that out what it is, what do you do?

So certainly the stimulants people use, but then they get worried about, well, are they going to cause problems with people with anxiety? And there's been some recent meta analysis that actually shows anxiety may get a little bit better. And it depends what you're looking at. Is it just panic attacks or worries? Yeah, I'm not sure.

They get a lot better. I think sometimes they can get worse. But then are you talking about avoidance of things because you have ADHD and cognitive problems? Well, those do get better. The net result of these meta analysis, sort of a study that looked at all the studies, is that treatment with psychostimulants actually significantly reduce the risk of anxiety compared to placebo.

But it doesn't rule out the possibility that some kids get worse. And I have to tell you, if you're a parent out there, of a kid or you're somebody with ADHD and you've had that experience. As a clinician, I see that all the time. So I think we're always looking to see, are we making things worse? But it used to be like, you can't use stimulants in those situations where there's anxiety.

And now we've rethought that that's been a shift in the field to say, no, go ahead and try them. Keep an eye on the anxiety. But it's not automatically, you can't use that class. My favorite go to, however, for anxiety and ADHD is adamoxetine. I described it earlier.

And what's remarkable is that there's real improvements in the treatments for the outcome for both ADHD and for anxiety. ADHD gets better, anxiety gets better. But again, a caveat about adamoxetine or strattera is that you, if you're going to use it, I recommend if you're thinking about starting it or if it's your child who's going to go on medicines, and you're like, do we start a stimulant or do we use strattera? I would say start with strattera, because strattera response, for whatever reason, and it's been replicated, it doesn't work as well. If you've been on a stimulant first, don't understand that, but that's that the other non stimulants doesn't matter if you've been on a stimulant first, but strattera does.

It's just not going to work as well. So if you're thinking of a new start patient, or if it's your loved one and you're thinking, what do we start with? If there's a lot of anxiety, give Strattera a chance. And then can you add a stimulant to strattera like I showed you earlier? Absolutely.

We use it for anxiety in ADHD, we use it for executive function. We use it for a lot of reasons. Now, I'm gonna jump into a very tough one, which is bipolar and adhd, and happy to answer questions about depression. We really don't have a lot of data with depression, it's really indirect data. And for depression and ADHD, we're either using a stimulant and a serotonin reuptake inhibitor for kids, because those are the only things that are approved, or for adults, we're using any antidepressant with that.

Sometimes we use bupropion, which is off label for ADHD, but is an antidepressant that does help ADHD and that does help mood. And we sometimes add to that, and sometimes we use tricyclic antidepressants, and they also help very well with ADHD and can help mood. And those are typically reserved more for adults. But when we're talking bipolar, we actually know quite a bit. And just to remind you, bipolar and ADHD have an overlap.

Many kids with bipolar onset in childhood have ADHD. If you're talking about adults with the onset of bipolar later in life, lower rates of ADHD, but there is a lot of overlap of bipolar. Severe mood dysregulation outbursts, manic activity, staying up at night, not sleeping the next day, the kids being very out of control when they have what we call mixed symptoms, both depression and mania at the same time. Severe temper tantrums that last all day, rage attack, destroying things. This is a group that's tough to treat.

What do we know about that? What does it look like? Let's start with just a case that gives you a sense of what that feels like. A 14 year old with longstanding ADHD who develops episodes of severe mood dysregulation, agitation and expanded mood, thinking they can take things on, they can do anything. Not just normal healthy narcissism, but really expanded, really thinking they can do things, jump fly, etcetera, along with some clear depressive episodes and poor judgment, making bad decisions, sexual decisions, spending, things like that.

A couple of things we've learned is number that probably the most important thing is get the bipolar disorder under control. Treat the bipolar disorder. Use mood stabilizers, you can use lithium, use antipsychotic class agents, you can use medicines like risperidone, arapiprazole, etcetera. There are a number of ways to treat bipolar disorder, but get that stabilized first. Once the bipolar is stabilized, you can then go back and add back treatments for ADHD.

So stabilize the mood and then move and work with treatments for ADHD. I'm just going to say, parenthetically, that anytime you're dealing with a severe comorbid condition, I'm talking about bipolar now, but depression would be the same. Anxiety, like panic attacks, things like that, substance use disorders, you really have to think about treating those disorders. And if it comes to a mood disorder like bipolar depression or anxiety, and it's really severe and the ADHD isn't as severe, treat the more severe condition first. And almost always, bipolar is more severe than ADHD.

And if you do that, you're more likely to have a good response to ADHD treatment, as opposed to if you don't treat that. So, looking at this, we're looking at the effect of trying to get a sense of what are some of the data and what does it feel like? Well, there's been data with methylphenidate, for example, in kids where if you take stabilized individuals with bipolar disorder, where their bipolar has been treated, and you try ramping up the dose, five milligrams twice a day, ten milligrams twice a day, or 15 milligrams twice a day of methylphenidate, using just a short acting preparation, what you see is no worsening of the bipolar disorder. Hey, that's great. Number two, you see a dose dependent improvement in the ADHD.

This is similar to a study that was done with amphetamine. We've had a couple of different studies, amphetamines, which was Adderall and methylphenidate. This was just regular Ritalin. What you see is improvements in the ADHD without activation of the mania. But that's nice at a small sample.

But what happens if you have a big sample? This has actually been studied in adults with bipolar ADHD in the Swedish registry study, and we all envy the Swedish registry studies because they can look at so many different components of care, including medicines that have been administered or psychotherapies that have been administered, and what people are getting and taking. They ask a simple question. They ask a question. If you started stimulants before the bipolar was stabilized, what happens to the bipolarity over time?

And if you started stimulants after the bipolar was stabilized, what happened? Well, what happens is if you start the medication, the stimulants, before you have good stability of the bipolar, I don't think anybody be surprised. The adults had manic symptoms. They got very bipolar, they got really revved up, etcetera. And that was found all the way to six months out.

In contrast, if you gave the medication to stabilize the bipolar, first they were stable, and then you gave the stimulant, what you found was improvements in the ultimate outcome. You actually saw less bipolar symptoms if the bipolarity was treated, and then you added a stimulant. So this is, again, part of the whole general. Anytime you have a severe co occurring problem with ADHD, you want to stabilize that and then treat the ADHD. In cases where there's more mild symptoms, let's say anxiety, where you're not really sure how bad the anxiety is, you know it's there and it could be part of the ADHD it's certainly worth trying to treat through it or trying to drug medicine like atomyoxetine.

So I want to summarize sort of this, the whole treatment refractory and say ADHD is common. It's associated with short, long term difficulties. And I think it's important that we realize that in cases where there's comorbid conditions or refractory ADHD, we have to treat the ADHD. It's not an option to say we're not going to treat it. You got to treat it because there's long term outcomes or negative, and treatment improves that.

There are multiple treatment strategies available for ADHD across the lifespan, the stimulants, the non stimulants, and often it's a dose issue or using the combination of a stimulant, non stimulant for refractory cases of ADHD and for comorbidity, often using that or other combinations. And then treatments exist for individuals with ADHD who also manifest cognitive. And we're working on that sort of executive function problems. We're working on that as we speak in psychiatric comorbidities and again, treat the more severe disorder. Often it's a combination approach that you're going to take psychotherapy medication, psychotherapy, multiple medication to get control of the comorbidity and the ADHD.

And I say stay tuned. New devices, psychotherapies. As we were chatting before we came on, for example, a new preparation of an extended release form of clonidine that you can give at night. Once a day, it's great. Give it at night, it works the next day.

That's now available. But we also have other medicines that are coming out, could come into market, like setanafidine, which offers hope because it may help some of the cognitive comorbidities. It also may help some of the anxiety and depressive co occurring problems with ADHD, given its pharmacologic properties. So it's exciting to be in the field. There's other medicines that are in development, other psychotherapies, digital therapies that may also work alongside some of our existing treatments to really help our kids, our adolescents, our adults get better with ADHD.

So with that, I'm going to turn this back over to see if we have some questions and hopefully some answers. Thank you. Thank you so much. Yes, we have lots of questions, but before we start the Q and A, I'd like to thank play attention once more for sponsoring this webinar. And I'd like to share the final results from today's poll question how has the ongoing ADHD medications shortage impacted your ability to manage ADHD and coexisting conditions?

Carol Fleck
Here's what you said. 19% said the shortage has had no negative impact on their lives, which is pretty surprising. 16% said it's difficult to find alternative ADHD meds that don't interfere with treatment for coexisting conditions. 16% said delayed access to medications has been a real problem and 15% said there's an increased reliance on non medication strategies. Now, to your questions.

Of course, we've had quite a few questions around ADHD and autism, which you address very well here. Some questions are, can ADHD medications exacerbate autism traits? Yeah, it's a great question. The answer is yes and anything. Anytime we're trying to treat, we're going to be monitoring that.

Speaker A
Did the medicines increase, for example, stereotypies, hand flicking, rocking, moving in a certain direction? Sometimes it's difficult to know, are we talking about a complex tick, a tick or a stereotypy? And we know that stimulants are not necessarily negative in context to ticks, but they can certainly make them worse in certain individuals. So, yeah, as a person, more restrictive, if the person had dysregulation, kind of losing it, frustration, did that get worse? So anytime we're using these medicines and individuals with autism, we're going to watch carefully.

We're not going to go up on the medicine as quickly, we're not going to go ramping up the dose really fast, we're going to do it slowly. We're going to try to get the right dose. In general, when you're using especially stimulants, you're trying to get to pretty much the higher doses because higher doses are going to give you best outcome. You're looking for the best outcome for kids with autism and ADHD, you're going to have to be a little bit more careful because you may not get to the best treatment for the ADHD, but a good treatment because if you go too high, you start having more side effects and it doesn't work as well.

Carol Fleck
Someone writes, our 19 year old son has ADHD, autism, very high anxiety and a mood disorder. When he has meltdowns, he gets aggressive and lashes out at my husband and me or he destroys part of the house. He's been on medication since he was six. How do we know if the ADHD meds increase his anxiety? And is there a place where we can take him to stop all his medications safely to see which he really needs?

Speaker A
Yeah. So that's a very complex case, and often, as you were indicating, you're going to be using complex pharmacotherapy. There's just almost no way around it in terms of your ladder point. You know, sometimes you can arrange for a residential program or a program like that where your son would be safe coming off the meds. You have to be very careful when you take kids off meds, and you want to be sure, as certain as you're tapering because of medical safety considerations, you don't want to stop them too quickly.

But the other option is these are often cases when there's mood, severe irritability, and autism. The medicines like the second generation antipsychotics like risperidone, arapiprazole, and others, those two are pruned, but there's other ones that don't have weight gain or other risks that can work very well. And those can help stabilize those outbursts, aggression. They can help a little bit with the ADHD, but they can also create a pocket then where you're safe to try stimulants or non stimulants for the actual ADHD. Lastly, about the anxiety.

Sometimes the anxiety can respond to more generic or benign medicines like busparone. We use a lot of that in autism and ADHD, where there's a lot of anxiety. You might want to try atomoxetine. That can help and help with the ADHD and others. And sometimes just using the antipsychotic class agents also helps with some of that anxiety.

But those are, that's a very tough case. It's going to require complex interaction. Okay, we had some questions around women's hormonal cycles. One question is, do you take women's hormonal cycles into account when adjusting meds for your patients? We talk about it in context to two major things.

Perimenstrual, like dysphoric issues. When women, and they're very tuned into this, feel like there's tremendous amounts of mood instability around the time of their cycles. And this is really independent of ADHD. There's ADHD mood, and then they'll say, it gets really bad around my cycle. Try to determine what makes sense.

And often in those individuals, we're using either medicine all the time or just during those times, or if they're on medicine all the time, they go up ten days before they cycle and then maybe down at the time of the cycle, and we have people doing that. The other is for kids who are starting younger kids or girls to women. Menarche, when are you starting your cycles? And we ask about that because that can have an influence. And then for women who are perimenopausal, there often are more symptoms of ADHD and other disorders.

And so we'll try to get that information also. So there's not one size fits all, but you're trying to take that into consideration. And then of course, people get put on birth control, different systems, but let's say any kind of an oral or a patch or any kind of technology like that, which can then further either exacerbate or improve mood symptoms. So kind of knowing all of that and getting that into totality does affect what you're going to be doing pharmacologically.

Carol Fleck
Someone asked, is there a best way to optimize ADHD therapy in menopause? Because my ADHD is worse now. Yeah, you have to oftentimes go, you know, there's a, it's sort of contrasting. People are getting a little bit later in their lives, their life burdens may be simplifying. So in many cases you could start reducing the meds for ADHD, and then you have a repeated finding and discussion by women that my symptoms are much worse now, my distraction, my inattention.

Speaker A
And then in those situations, we're often increasing the doses of medicine. So there's this countervailing force that I think you need to take into consideration. At the end of the day, if you're sitting, when you're sitting with your practitioner, if your ADHD is not well managed, certainly talk to them about what are your options, increasing dose, shifting preparation, trying something else. But it is a common conversation that we have, so you're not alone. And I think staying in close contact, whoever's treating your ADHD, will make it much better.

You can't sit and suffer with a lot of symptoms. Dose.

Carol Fleck
Someone says, how do I convince my doctor to prescribe combination therapy for my ADHD? They're very reluctant. First of all, I would say talk to them about, first of all, certain combination therapies are FDA approved, so stimulants plus clonidine or Guan fasting are FDA approved. So they wouldn't be FDA approved unless they were both effective and safe. And I know the studies actually did one of them studies so well aware of that.

Speaker A
Number two other combination therapies have been used and published. So, for example, if you're using strattera in a stimulant, there have been over ten studies on that. So there's a lot. If you're using other combinations, I think the most important thing is to realize that most medicines we use for ADHD are safe in combination with other men. Some you may have to reduce or be mindful of, such as strattera or voloxazine.

With certain medicines, if you're using stimulants, there's really no drug, drug interactions to worry about. They actually don't, like, at a drug, drug level, increase the levels of another drug or another drug doesn't increase the levels of stimulants. There's no, we call it pharmacokinetic. It's a technical way of saying that there are no pharmacokinetic drug interactions with stimulants. They're remarkable that way, quite honestly.

So they're safe pretty much in combination with other medicines. So if you're on an antidepressant or if you're on even a big gun, like a second generation antipsychotic or medicine like newspart for your anxiety, it's okay to do that. Okay. Someone asked, can combination therapy help treat high risk behavior in teens and young adults? Yeah.

So that's a great question in a preventive way. I sort of think of high risk behaviors as sort of impulsivity driven, usually, and the medicines alone, like stimulants for ADHD. Anytime you're treating ADHD, you're reducing impulsivity and you're helping high risk behaviors for kids who have increased amounts. Let's say they don't have ADHD, like conduct disorder, which is, you know, kids who don't have the same values, societal values, harm other kids, harm animals, aren't as concerned about. They're aggressive.

Usually when they're very young, they get into fights, et cetera. Those kids actually even do better with treatments that we use for ADHD in kids who have the combination of, let's say, delinquency and high risk behaviors with ADHD tend to do better when you treat the ADHD. Just treating ADHD helps high risk behaviors. In fact, long term data, that's another talk at some point. We've done studies on long term outcomes.

Virtually all of these long term outcomes that we know occur with ADHD, pregnancy, motor vehicle accidents, traumatic brain injury, injuries in general, substance use disorders, all of those things that are double or tripled with untreated ADHD. If you treat ADHD over the long haul, you see those go back to almost population rates. It doesn't immunize you. It's not like you're still at risk, but like anybody in the general population. So I'm glad you mentioned that treatment of ADHD really does help many high risk behaviors over time.

Carol Fleck
Wow, that's great information. We had a few questions around food addiction and eating disorders. What's the best treatment for ADHD and eating disorders? Yeah, it's a great point because we didn't talk about eating disorders, but there's an overhead over representation of eating disorders and ADHD. And if you start with eating disorders, you see your higher rates of ADHD.

Speaker A
And pretty much if you work with eating disorder patients, pretty much anybody with really severe eating disorders has tremendous cognitive impairment, something that's very notable. So having said that, we strongly recommend, like any co occurring problem, that it's addressed that they're in treatment for eating disorders or they're dealing with it. And then you can treat the ADHD. And a lot of people say, wow, they're anorectic. Can we use stimulants?

Well, you can try non stimulants first. A lot of people like to do that. Adamoxetine, voloxidine. Some people use tricyclics, other things like that. But can you use stimulants?

The answer is yes. For some cases, like a lot of eating disorders are mixed. They have some restrictive eating and then they have some binge purge activity. And the binging where, you know, where you eat and then you throw up, that whole cycle gets improved and is FDA approved to be using medicine by bands that's been FDA approved for binge eating disorder. So for people with binge eating disorder and ADHD, you can go right to a stimulant medication.

So again, address the eating disorder and treat. You can treat the ADHD and often you have to. And I've done that in a number of cases and found a lot of successful outcomes there. I got to tell you, a lot of people, I've treated younger people, of course, and in their teens, and then I've followed them through college and they've done really well. I'm really struck.

But they do need the treatment for their ADHD. They're the first ones to say, I've got to get the ADHD treated and we will keep an eye on their weight, we keep an eye on their calories. If they're still purging and stuff, we'll keep an eye on potassiums and stuff. You have to monitor certain things. But I have a number of people who are no longer in treatment for eating disorders, but are doing very well now in their later twenties.

So I think it's a good outcome, this combination. But you really have to address eating disorder at some point. Okay. We had a few questions around emotional dysregulation and frustration management, how best to treat those. Yeah, so, you know, part of ADHD is frustration intolerance.

It's a symptom. And then a number of people, Paul Wender, the person who did a lot of ADHD research in adults, Russ Barkley. Others have talked about emotional dysregulation as a component of ADHD. It's not other than one symptom. It is part of ADHD symptomatology in some ways, because you see it all the time.

Management is treat ADHD if you're treating it pharmacologically. People have a lot of frustration intolerance, anger management, anxiety management. But they're very similar, by the way, in approaches can be really wonderful. I think a course of sort of a resiliency training or cognitive behavioral therapy that is directed at how to manage anger frustration, how to identify when it's first occurring, how to release yourself from that, what to do once it's starting to boil up, what do you do? Stop being dysregulated.

All of those things are components of a cognitive approach to anger management. Then there's other kinds of therapy that help introduce mindfulness, resiliency, dialectic, behavioral. But I think those are helpful for people with a lot of it. Treat the ADHD if it's still there. There's data, for example, that low doses of second generation antipsychotics like risperidone can help.

Randomized controlled trials at those medicines at low doses can really help eliminate that. Okay. Someone writes, my husband is a runner. He's 49 years old. He has adhd and anxiety, and his heart rate increases on stimulants and even on strattera.

Carol Fleck
Are there other options that won't increase his heart rate? Yeah, it's a great point. Voloxazine is something to think about. You may want to try even a tricyclic. But most of the medicines we use for ADHD, increased heart rate.

Speaker A
Other thing they do, we did a study, a three dimensional cardiac imaging study, and graded exercise testing. And what we found was that it didn't cause damage to the heart. In fact, it looked like a conditioned heart after six months on medicine, very similar to football teams. But to your point, something that I actually talk about, because I work with athletes, is it's called heart rate recovery. And that is, how long does it take your heart to slow down after you do physical activities?

You know, if you run sprints or if you're out there on a fast walk, or if you're really lifting weights or you're swimming or you're doing anything, you're skiing hard, your heart rate goes up, and then it comes down pretty quickly. Stimulants prolong heart rate recovery. It takes longer for your heart rate to come down. So that's one of the things to think about, that that's just going to happen. There's not much you can do about it.

When I work with hockey players, cross players, things where there's a lot of sprint swimmers, I tell them it's going to take longer, and it doesn't mean you're deconditioned. And our cardiologist colleagues who reviewed those data said that it's not putting you at increased risk for any kind of negative outcomes in terms of your husband. There are things we've done when we've had elevated heart rates that can sometimes help slow them down. We sometimes give a class of medicines called beta blockers, like propanolol or inderalol. We use that for ADHD when it causes a lot of grinding, when there's a lot of tension.

For people who say that their heart rates go up and they don't like that feeling, and we usually do it after they've seen their primary care doctor or cardiologist, where they say there's no pathology under racing heart, especially much above 100 2140. For somebody out of stimulant, you really need to go see somebody to say, that shouldn't happen. It could be signaling there's something else underlying. Let's say you have that workup, it's normal. Then we add beta blockers, and that really helps cut back that.

Sometimes in kids, we use the alpha agonists like clonidine and guan fasting. It turns out those slow the heart rate also. Can you use those in adults? You can, but there was a study in adults using guan fasting, extended release. And I think it's like 20% of the people dropped out because of their heart rates, went so slow that they started feeling, like, dizzy.

So it's not always the best intervention to use an alpha agonist, but beta blockers can work. Okay. And we had a few questions around OCD and ADHD, how to best treat those. Yeah, that's. Yeah.

To remind people OCD is obsessive compulsive disorder. Either have a lot of thoughts that are bothersome, that are hard to get rid of, or rituals that you're doing that repeat that you have to do to release anxiety that are also cause distress. And what we found is that if you start with OCD and you look at the rates of ADHD. About 50% of kids with OCD have ADHd. A lot smaller group of kids with ADHD have OCD, but a lot of people with OCD have ADHD, and you really don't know it until you treat the OCD.

The treatments for the OCD are, you know, certain types of psychotherapies can be very helpful, and then using medications. And the medicines that work the best are serotonin specific reuptake inhibitors, SSRI's for serotonin, norepinephrine reuptake inhibitors, snris in that order. SSRI's a little bit better than snris, but those work. And afrinil, you can treat the OCD and then you go back and treat the ADHD. And if you have good control of the OCD, it's similar to pretty much every other comorbidity.

If there's good control of the co occurring problem, then you can go and treat the ADHD. You can use stimulants or non stimulant medicines. I have a number of individuals I've treated my life who have OCD, ADHD, and again, very rewarding outcomes. You get both of them under control and they do much better in life. I will say that it's not like you just pick a medicine and that's it.

I mean, it's always coming back and they're doing fine for six months, a year, two years, and all of a sudden, something's gotten worse. Part of it is OCD cycles, anxiety cycles. It's not like it's always at a certain level, it's better, it's worse at different times, and you're going to have to manage that by upping or decreasing your medicines. And then sometimes another sort of clinical pearl is it's not uncommon that people come to me and say, I need to get my. I have comorbid, whatever, depression, mood, OCD, anxiety, and my ADHD all of a sudden got worse.

And sometimes what it is is it's actually the co occurring disorder is getting worse. And if that gets worse, the ADHD gets worse, and all you have to do is treat the co occurring problem, get that under control, and the ADHD treatment works again. So it's something that we've learned, and we actually published a paper almost 20 years ago about that phenomena. So if there's another disorder with ADHD and that disorder starts to destabilize or get a little bit worse, by which happens the ADHD treatments that was working beautifully doesn't work as well. Rather than muck around and go to high doses of your ADD treatment, remember to keep an eye on the co occurring problem because that may be what the offender is.

Carol Fleck
Okay? Such great information. Thank you so much, Doctor Willans, for joining us today and for sharing your expertise with our ADHD community. Thank you so much for having me. And thank you to today's listeners.

If you would like to access the event resources, visit attitudemag.com and search podcast number 508. The slides and recording are posted a few hours after each live webinar. If you're listening in replay mode, simply click on the episode description and please know that our full library of Attitude webinars is available as a podcast. It's called the ADHD Experts podcast and it's available on all streaming platforms. Make sure you don't miss future attitude webinars articles or research updates by signing up to receive our free email newsletters@attitudemag.com.

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508- Combination Therapy: Medication Strategies for Hard-to-Treat Complex ADHD

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1: Introduction

2: Medication Overview

3: Addressing Comorbidities

4: Future Directions

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