Evolving Perspectives on Neurotransmitter Systems in ADHD

Leading psychiatrists explore the evolving neurobiological basis of attention-deficit/hyperactivity disorder (ADHD) symptoms and how it can inform integrative approaches to treatment. After watching the video, test your knowledge with the quiz in the sidebar. 

To learn more, view the full series: ADHD Beyond The Core – What We’re Missing and Why It Matters. 

Cutler: Hello and welcome to this section in our series on ADHD and the unrecognized symptoms. We're going to be talking in this section about evolving perspectives on neurotransmitter systems in ADHD. We know—for a long time we've had lots of evidence, both from neurobiologic studies and from what kinds of medications seem to be effective, that dysregulation of norepinephrine and dopamine are really critical, important underlying neurobiologic features of ADHD. However, we are learning more and more about the role of the other monoamine, if you will, the neglected monoamine in ADHD, which is serotonin. And it turns out that these 3 monoamines really have a very important interplay with each other and need to balance each other out. They're very interconnected. Their circuitry is interconnected. The receptors are interconnected. For instance, you can have a serotonin receptor on a dopamine neuron and vice versa. So, they really are all interplaying, and we are really understanding ADHD now as more of a dysregulation disorder.  

It's not too little norepinephrine or dopamine. It's there's something wrong with the circuitry, with the connections of parts of the brain, with the modulation, with the delicate dance between the top part of the brain—the prefrontal cortex that has to do with executive function and higher functions—and the lower part of the brain, kind of the limbic system, emotions, aspects that have to do with sustaining attention. It's just not all connecting properly. Now, let's talk specifically about some of these neurotransmitters. When we're talking about norepinephrine, this is involved with attention, arousal, mood regulation, signal detection—and let me, guys, explain what that means. To pay attention to the sound of my voice, you have to do 2 things. You have to register and process the sound of my voice, the signal. But we also have to gate out irrelevant noise, irrelevant signals. And norepinephrine appears to be related to the signal, and dopamine is a little more related to decreasing the noise.  

So, it's a signal to noise balance. But also, norepinephrine is involved with stress response and resilience, which are all, of course, processes central to ADHD. And I've been saying for a while, ADHD is much more than just dysregulation of attention or of behavior. It's also dysregulation of motivation, reward, and of the arousal system, circadian rhythm. We know there's a very high association of sleep disorders and sleep dysregulation with ADHD as well. So, again, thinking about the whole patient and really a comprehensive management plan is important. Now, let's move on to dopamine. Dopamine is near and dear to my heart. That was my research training. But the dopamine system is involved in a whole host of things with ADHD such as motor activity. We sometimes forget, dopamine is involved with coordination of movements, for instance, clearly mood. And then, aspects of cognition, attention, learning, memory, and the motivation reward system importantly.  

And, of course, all of these can appear dysregulated clinically in our patients. Now, we also know that all 3 of these monoamines have been implicated in depression and anxiety. Our medications that have been shown to work for depression and some of the anxiety medicines have been thought to be working through these monoamine systems. I want to focus a bit now on the serotonin system, which really is coming into play a little more. Our understanding now involves that we used to think of serotonin just for depression and anxiety, but it turns out not only may it be associated with some of the associated features such as emotional regulation, serotonin may be involved in some of the core symptoms of ADHD. For instance, we know serotonin is involved with impulsivity, but it also can be involved with areas of cognition including social cognition, also stress-related cognition, which people with ADHD we know don't always do well with stress.  

Now, how does this system work? Well, serotonin, particularly in the prefrontal cortex and amygdala are very important to have in balance. And this can, again, be involved with mood, impulse control, and overall emotional regulation. Serotonin neurons, like the other monoamine neurons, project up and innervate virtually every part of the brain it seems like, including—but particularly relevant to our discussion—the prefrontal cortex and the striatum, which also you can think of as the limbic system. And it's where motivation, reward, anxiety, and mood, depression kind of sit. Serotonin receptors, as I mentioned earlier, also modulate the other monoamines. Serotonin receptors can sit on dopamine neurons and norepinephrine neurons, and there's a lot of crosstalk. So, this suggests that all 3 may have a role to play, and maybe we've been missing the boat a little.  

The minimum number of legs you have to have a stable stool is 3. And I think we've only been looking at 2-legged stools to—I'm using my friend Rakesh’s kind of analogies. He taught me how to use these analogies. So, I think now serotonin is starting to be looked at. There have been some articles and some research into this area as well. And so, just as we're thinking about comprehensively treating a patient in all of the symptoms and associated comorbidities, maybe we need to think more comprehensively about the neurobiology of ADHD and how to treat that. Greg, let's talk a little bit about some of the consequences of the role of all 3 neurotransmitters and how they play and what can that look like clinically?  

Mattingly: Andy, you and I, and honestly all of us, we've been involved with research taking a look at not just these monoamines but specific receptor subtypes for them. And we know that there's a delicate interaction between them. We know that serotonin isn't just serotonin, but serotonin modulates dopamine through crosstalking networks. We know that norepinephrine transporters also cotransport dopamine in the prefrontal cortex, so it's not one or the other. It's the interaction of all of these. I think we then have to step back from neurobiology and look at what we see as phenomenology within our patients. So, Rakesh, we've talked about the associated features such as poor frustration tolerance in response to stress—“I'm good on a good day, but I just lose it on a bad day or a tough day”—feeling demoralized, feeling overwhelmed, or just being out of control. Desiree, I think that's why a lot of women come in with a chief complaint of feeling stressed and overwhelmed. “I feel like my life is in imbalance. I feel like I don't have good emotional control of my life. And I know it's driven by something that's been there since I was a kid, but it's been building over time throughout my life.” So, I think we're getting to a more elegant, nuanced understanding of ADHD. And I think the neurobiology helps us to understand the phenomenology of what we see with our patients.  

Cutler: Boy, I really like what you said, Greg, and I think we don't focus enough. You talked about demoralization. I think we don't focus enough on self-esteem. If you think about it, these are people who just throughout life keep meeting with failure and negative feedback and problems with relationships and work and school. And Desiree, it seems to me that this self-esteem issue is such a big issue that we don't just want to confront this with pills and medications. We probably have to look more holistically.  

Matthews: Absolutely. And I think a lot of this becomes internalized over time. And I think having an understanding and a more nuanced understanding of the neurobiology of ADHD and being able to actually talk to patients and families about it, I think can be very validating. Because sometimes people come in, “I don't have ADHD, I'm not hyperactive.” Maybe they're not fitting quite in this neat little box of the DSM-5 and kind of our core criteria. So, it can be really validating to acknowledge that there's something beyond these core symptoms that “I'm just not a hot head. I'm just not overly emotional for no reason.” That there could be an explanation for it. So, I think it's very nice for patients to hear these things from us, because like I said, we thought about ADHD in boys and the hyperactivity, so I get a lot of that from women. They're very appreciative of hearing this.  

Cutler: Yeah, ADHD used to be conceptualized as hyperkinetic disorder of childhood, but really the criteria were written for overactive boys. And so, we've come a long way. But what this also highlights is the heterogeneous clinical presentation. One of the funny things about ADHD is you don't have to have the “H” to qualify for the diagnosis, especially, as we mentioned, in women. But I think also thinking about the clinical heterogeneity helps me understand that there's a lot of neurobiologic heterogeneity. One of the things, Rakesh, I struggle with, especially if we're talking about anxiety, is what's the chicken and what's the egg? Because clearly, to me, if somebody is forgetful and losing things, getting negative feedback, anxiety creeps in, but they can also have primary anxiety. So, how do we sort that out?  

Jain: Oh man, 2 lines of thought we can have. One is genetics. The genes that are involved in the pathogenesis of ADHD and the genes that are involved in the pathogenesis of anxiety seem to travel on the same arm of the chromosome. So, either you get both or you get none. So, that's factor 1 to keep in mind. The other is what is anxiety, if not a misperception of how the world is reading you? That's what anxiety is in some ways. And if the feedback loop—which, by the way, builds confidence—is broken, and the feedback loop constantly from the world, the mirroring, is you're inadequate, you're failing by default, a sense of low self-esteem, a low confidence must develop. And that gets interjected into the self. And now you're constantly on guard trying to protect. We call that anxiety. So, a thoughtful clinician like we are, and we're asking our colleagues to be, appreciates that anxiety, sadly, is the fallout from undiagnosed, untreated, ADHD. And if you're thinking about ADHD, to not think about anxiety is a clinical mistake of the first order.  

Cutler: I would agree. I think we've focused a lot on depression. We've done a good job talking about depression. But anxiety, to me, feels like a little more of a forgotten comorbidity, a forgotten bad friend, as Greg said, if you will, comorbidity. So, I'm glad we're talking about this and thinking about the neurobiology. And that may, of course, inform our thinking about what medications, what treatments, and even some holistic kinds of other things we can bring to the table. So, thank you for a wonderful discussion. Thank you. Hopefully this was valuable to you as well. And please keep following all the other segments in our series.  

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Andrew Cutler, MD 
Dr Andrew J. Cutler is a clinical associate professor of psychiatry at SUNY Upstate Medical University in New York, and he serves as the chief medical officer of the Neuroscience Education Institute. He received his MD from the University of Virginia School of Medicine, where he was also elected to the Alpha Omega Alpha honor medical society and received the Merck Award for outstanding medical scholarship. He completed his medical internship, internal medicine residency, and psychiatry residency at the University of Virginia Medical Center, where he served as chief resident of psychiatric medicine and did research on dopamine receptor pharmacology.  Dr Cutler then served as the first assistant professor and director of psychiatric medicine at the University of Chicago.  He is board certified in both internal medicine and psychiatry. Dr Cutler has also been the principal investigator on over 400 psychiatric and medical clinical trials.   

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Rakesh Jain, MD, MPH
Dr Rakesh Jain is a clinical professor at the Texas Tech University School of Medicine. He attended medical school at the University of Calcutta in India. He then attended graduate school at the University of Texas School of Public Health in Houston, where he was awarded a “National Institute/Center for Disease Control Competitive Traineeship.” His research thesis focused on the impact of substance abuse. He graduated from the School of Public Health in 1987 with a Master of Public Health degree. Dr Jain served a 3-year residency in Psychiatry at the Department of Psychiatry and Behavioral Sciences at the University of Texas Medical School at Houston. He then obtained further specialty training, undergoing a 2-year fellowship in child and adolescent psychiatry. In addition, Dr Jain completed a postdoctoral fellowship in research psychiatry at the University of Texas Mental Sciences Institute in Houston. He was awarded the “National Research Service Award” for the support of this postdoctoral fellowship. 

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Desiree Matthews, PMHNP-BC 
Desiree Matthews is a board-certified psychiatric nurse practitioner with expertise in treating patients living with severe mental illness. Beyond clinical practice, Desiree has provided leadership in advocating for optimal patient outcomes and elevating healthcare provider education. Desiree is the founder and owner of Different MHP, a telepsychiatry practice founded with the mission of providing affordable, accessible, precision-focused, integrative psychiatry to patients through a rich and comprehensive mentorship of the health care providers within the company. 

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Greg Mattingly, MD 
Dr Greg Mattingly is a physician and principal investigator in clinical trials for Midwest Research Group. He is also a founding partner of St Charles Psychiatric Associates and an associate clinical professor at Washington University. A St Louis native, he earned his medical degree and received a Fulbright scholarship while attending Washington University. Dr Mattingly is board certified in adult and adolescent psychiatry and is a diplomat of the National Board of Medical Examiners. Dr Mattingly has been a principal investigator in over 400 clinical trials focusing on ADHD, anxiety disorders, major depression, bipolar disorder and schizophrenia. Having served on numerous national and international advisory panels, Dr Mattingly has received awards and distinctions for clinical leadership and neuroscience research. Dr Mattingly is also the President for the American Professional Society of ADHD and Related Disorders and is on the Scientific Advisory Board for the World Federation of ADHD.  

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