Myths and Facts About the Safety of Treatments for ADHD and Its Comorbidities

In this video, Vladimir Maletic, MD, MS, speaks with Greg Mattingly, MD, about recent research on the use of medications for attention-deficit/hyperactivity disorder (ADHD) in patients with comorbidities such as anxiety disorders, mood disorders, and tic disorders.

Dr. Maletic is the ADHD Section Editor for the Psychiatry & Behavioral Health Learning Network and a member of the Psych Congress Steering Committee.

Read the transcript:

Dr. Vladimir Maletic: Hello and good afternoon. My name is Vladimir Maletic. I am Clinical Professor of Psychiatry at USC School of Medicine in Greenville, South Carolina.

Joining us this afternoon is Dr. Gregory Mattingly. He is Associate Clinical Professor at Washington University's School of Medicine in St. Louis, Missouri. He is also president of Midwest Research Group in St. Charles, Missouri. He is on the board of directors of APSARD [the American Professional Society of ADHD and Related Disorders]. Thank you very much for finding time to join us today, Greg. We really appreciate it. We have several questions for you.

Dr. Gregory Mattingly:  Let's go.

Dr. Maletic: I am aware that you have recently published an article. The article focuses on some very relevant but controversial issues regarding ADHD medications.

Typically in their package inserts, aside from cardiovascular warnings, there are warnings about these medicines used in patients who have anxiety disorders, potential for greater irritability, controversial use in mood disorders, tic disorders, and so forth.

I would be curious to hear from you. You have studied the subject in detail. Could you provide some commentary when it comes to use of ADHD medications in patients who do have anxiety disorder, tic disorders, and mood disorders, given that these are common comorbidities of ADHD. What are your thoughts?

Dr. Mattingly: Thank you for having me here.

The article you referenced was a group of 4 of us that came to ADHD from very different walks in life. One is an addictionologist who's an MD/PhD who does a lot of work with ADHD. One is somebody who comes from a multinational background, having been born in South America. One is a child psychiatrist who does a lot of inpatient psychiatry.

We all said that this complex nature of ADHD is something we haven't talked much about. How do you break it down, as you said, in someone who has depression plus ADHD? The old adage was treat the depression first and then only treat ADHD if there's something left over.

We now have studies from here in the United States and studies around the world that said combined treatment, treating ADHD at the same time that you treat the mood disorder, quite often gives the best outcome for your patients.

Similarly with anxiety disorders. We know that anxiety is the most common comorbidity for a woman or a teenage girl with ADHD. Quite often, if you just treat the anxiety, but ADHD is driving the anxiety, if ADHD is driving the sense of loss of control, distractibility, feeling overwhelmed, anxiety treatment by itself doesn't work very well.

We talked about this holistic approach of combined treatment for these combined problems.

Dr. Maletic: Have you encountered ADHD symptoms getting worse? There are package inserts suggesting that especially use of stimulants may worsen anxiety. What would be your response to that question?

Dr. Mattingly: Once again, if ADHD is the underlying condition, if it's the original condition that's driving the bus, then quite often treatment with low doses of sustained release ADHD medicines can be very beneficial for our patients, not just with cognitive symptoms, but the emotional processing of their anxiety.

Dr. Maletic: I know that you often quote a study, a number needed to treat, that use of ADHD medicines can actually be associated with a positive outcome in treatment of anxiety.

Dr. Mattingly: Correct. Joe Biederman and our friends at Harvard published what I think is just a wonderful clinical study that said, "How many people do you have to treat to prevent one negative health outcome?" Typically, in medicine, that number needed to treat may be 10 or 15. 10 people on a statin to prevent one heart attack.

In this case, they said, "How many people do you have to treat with an ADHD medicine to prevent a negative health outcome in life?" Instead of 5, 10, 15, what they found, it was quite often 3 or 4.

For every 3 to 4 people we treat for ADHD, we prevent one from developing a bad anxiety disorder, one from developing a bad mood disorder such as depression, one from having an encounter with the law because of difficulties with life and modulation of their emotions and affect.

Dr. Maletic: Talking about encounters with law, sometimes substance abuse is involved. That has been a tricky question. What about individuals who have, in the past, abused substances? It's not uncommon in teenage population by any means. As a matter of fact, it is one of the more common comorbidities of ADHD.

Especially in our primary care colleagues, there's a lot of concern that if we use stimulants to treat ADHD, is this a gateway for our patients to start using substances?

Twofold question: Is it still OK to use stimulants in somebody who has a history of substance use? In doing your research, what have you found?

Dr. Mattingly: I'll point out 2 of the studies that I think are very relevant for this. One is go back to Dr. Biederman's study. For every 6 to 10 people that you started on ADHD treatment, you prevented one from going down a life of having substance use disorders.

If a child is decompensating, he winds up with the wrong peer group because he doesn't feel good about himself, we know that that leads you down a very difficult path in life. Preventative treatment actually helped to deter some of those bad encounters.

There's a landmark study that just came out by Tim Wilens and his group at Harvard where they looked at people that were in substance use treatment but had ADHD. They said does treating the ADHD improve or does it destabilize the treatment of the substance use disorder going on?

What they found is, and I think you and I have talked about it, you were 3 times more likely to stay in ongoing substance use treatment if your ADHD was being treated at the same time.

Dr. Maletic: So, in general, very little risk of harming the situation further and quite a bit of evidence that actually it may ameliorate the risk of relapse and continued substance use. Thank you for that comment.

Another study that brought up a lot of questions, it is a recent study. I'm sure you're aware of it. It was a study that encompassed in excess of 1500 patients who suffer from bipolar disorder and schizophrenia.

Some of these individuals, as a matter of fact, about 15 percent, were also subsequently diagnosed with ADHD. About 1 in 5, actually had ADHD as a comorbid diagnosis.

We are cautioned against using stimulant medications in individuals who have risk for psychosis as may be the case with bipolar and schizophrenia. In this study, it was noted that treatment had a surprising outcome when it came to suicidal attempts and self-injurious activities.

Would you comment on this? Let me ask you directly a clinical question. How do you feel and what is your thought process when considering ADHD medicines, including stimulants, in patients who have bipolar and schizophrenia?

Dr. Mattingly: Vlad, I'll have to say my thinking has evolved quite a bit there in the last 20 years. I would have taught my medical students, and my residents, and my fellow clinicians that's a place where we avoid stimulants.

But the data's come out showing something very different. The data has shown that very careful use in that population can help to stabilize impulsivity. We know that in this group that has ADHD plus bipolar, ADHD plus other symptoms, impulsivity quite often is one of the most damaging aspects of the illness.

So very careful, very cautious, very appropriate use has been shown to decrease impulsive suicide attempts. It's been shown to help stabilize impulsivity within people's lives.

I've been a part of 2 adolescent bipolar studies where we asked that very question. If you have ADHD originally but now you have bipolar, is it better or worse to stay on your ADHD medicine? The answer from both of those adolescent bipolar studies is the children who stayed on their ADHD medicine had the best outcomes when we treated their bipolar disorder.

Dr. Maletic: What I hear you saying, it is good to have a foundational mood stabilizing agent or an antipsychotic in case of psychotic disorders, but using stimulant in ADHD medicines that ameliorate impulsivity may be beneficial.

I believe that is actually one of the conclusions in the study, is that improvement in risk of suicidal attempts was directly correlated with suppressing impulsivity.

Given that at least 3 out of 4 individuals who have ADHD have comorbid conditions and they do include anxiety disorders, and substance use, and mood disorders. Is there anything new on the horizon? Is there anything that may influence our approach to treating ADHD and comorbidities at the same time, as you suggested may be prudent in some instances?

Dr. Mattingly: Certainly, as you know, in the last 27 years I've been a part of probably a hundred different research clinical trials in ADHD. Children, adolescents, adults. Taking short-acting medicines. Making them long-acting medicines. All different versions.

The Holy Grail has been to find some nonstimulant medicines that may improve certain outcomes for our patients. There's several molecules on the horizon that are going to have different mechanisms of action.

One of those is a triple reuptake inhibitor named centanafadine. It's going to block the reuptake of serotonin, norepinephrine, and dopamine. It's going to come to us with a novel mechanism of action. Its original trials were in adult ADHD. It's now working itself into the pediatric space.

The newest medicine to just get FDA approval, just last week, Vlad. What was it, Thursday [April 2, 2021], I believe?

Dr. Maletic: It was Thursday or Friday, somewhere in there.

Dr. Mattingly: Sustained release viloxazine. This medicine comes to us now with an FDA indication for children aged 6 to 17 and modulates the norepinephrine reuptake pump, but it also modulates several serotonin receptors that directly increase the levels of synaptic serotonin.

I know you've done a lot of the research on this, Vlad, and you're written a review article about the mechanism of action. Having been a part of those trials, I have used it for children. I've used it for adolescents. It just has a different feel than what we currently have on the market.

Dr. Maletic: I believe that, in the past, this medication under a different name and not an extended-release form was also approved in Europe for treatment of [major depressive disorder]. There actually is some evidence.

What I hear from you is there are a couple of promising agents. We really need good empirical data providing information about what these medications may do in patients who have ADHD and comorbid mood disorders or anxiety disorders.

At least there is something to be intrigued about, something to be curious about. With that, Greg, I really thank you for taking time to join us this afternoon, as well as your very thoughtful and thorough answers.

I hope all of you have enjoyed this program. I wish you all a good day. Thank you very much.

Dr. Mattingly: Take care.