Monday, September 25, 2023
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Editor's note:
Research into the genetics and neurobiology of ADHD is advancing rapidly, and with it, our thirst for more effective, highly
targeted treatments for attention deficit-hyperactivity disorder (ADHD). How much do we really know about the genes and neurochemical
processes that
form the underpinnings of ADHD? How close are we to realizing truly individualized therapies? To sort out these and other
questions, and on behalf of Medscape, Craig Surman, MD, went to the source of much of the research on ADHD genetics and neurobiology,
Stephen V. Faraone, PhD, Director of Medical Genetics Research, and of Child and Adolescent Psychiatry Research at the State
University of New York, Upstate, in Syracuse, New York.
Take this interview with you!
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Craig Surman, MD: Hello and welcome. I'm Dr. Craig Surman, Instructor of Psychiatry at Harvard Medical School and the scientific coordinator of the adult ADHD research program at Massachusetts General Hospital in Boston.
It is my distinct pleasure to speak with Dr. Stephen Faraone, who is Professor of Psychiatry, and of Neuroscience and Physiology at the State University of New York, Upstate, in Syracuse, New York.
This interview coincides with the 2007 meeting of the American Psychiatric Association (APA) in San Diego, California. We will discuss the neurobiology and psychopharmacology of ADHD, particularly in the context of some studies that are being presented at this meeting this year.
Dr. Faraone, ADHD is said to be one of the most heritable of mental health conditions. Could you comment on evidence for environmental vs genetic causes for ADHD?
Stephen Faraone, PhD: We now have decades of research in the genetics of ADHD, and we can say with certainty that genes play a substantial role in influencing the etiology of ADHD. This is without a doubt. In my last review,[1] we analyzed 20 twin studies of ADHD and computed a heritability of 76%. Now, that's a figure that's technical and somewhat difficult to understand, but generally it tells us that genes account for a substantial portion of ADHD -- roughly 76% of the etiology.
That does not mean that the environment is not important. We know that the environment accounts for the other 24%, but we also know that the environment interacts with some of those genes that are responsible for the 76% of the variability, so both genes and environment are important.
Most of the environmental agents that have been implicated tend to involve prenatal or perinatal adversity to the child, obstetric complications in the mother, toxins such as exposure to nicotine, the mother drinking alcohol, polychlorinated biphenyl exposures as some examples. It's important to note that all of these effects are small effects. When I say this sometimes a mother gets worried because she was drinking during pregnancy and thinks that she's condemned her child to have ADHD. That's not true. Most mothers that drink don't have ADHD children. It's not an endorsement of drinking during pregnancy, but the point is that these risk factors and genes each have very small effects that cumulatively add up to stress the brain to lead to the disorder.
Dr. Surman: Are there specific genes that you would say might cause attention deficit disorder?
Dr. Faraone: What I would say is that there are several known genes that I like to think of as susceptibility genes for ADHD. There's no single gene. There's no magic bullet. There's no one gene that causes ADHD and that alone causes the disorder, but there are several genes [that enhance susceptibility]. For example, the dopamine transporter gene has been very well studied, and we have strong evidence suggesting it's involved in ADHD.[2] The same is true for the gene that encodes for the dopamine D4 receptor, and the dopamine D5 receptor.[2] There's good evidence for a gene called SNAP-25, which stands for synaptosomal protein of 25 kilodaltons.[2] It's a mouthful of a name, but it's a very interesting gene because it controls synaptic vesicle transmission -- what happens at the synapse -- and we believe that at some level ADHD is a disorder of the synapse.
Dr. Surman: How might those genetic findings fit into the 'catecholamine hypothesis' of ADHD?
Dr. Faraone: The catecholamine hypothesis basically states that dopaminergic and noradrenergic pathways in the brain are responsible for the symptoms of ADHD. What we've seen in the genetic studies is that certainly in the dopamine system genes -- and I've already mentioned 3 dopamine genes that are responsible for some of the genetic etiology of ADHD -- those fit very well into the catecholamine hypothesis. The genes I mentioned are the ones that are most confirmed for ADHD, but there are others as well. For example, in recent work that we've done and others it seems that the norepinephrine transporter gene is implicated.[3]
Now, it's interesting that many of the genes implicated are directly related to the medications that work. For example, methylphenidate and amphetamine both work at the dopamine transporter. Atomoxetine works at the norepinephrine transporter. Of course, that's how we chose which genes to study, so it's not simply a coincidence. We chose those candidates because we knew they were involved in ADHD relevant systems.
Dr. Surman: What are the implications for treatment? You mentioned already that some particular medications that may target the catecholamine system neurobiology, but do different agents target those system elements differently?
Dr. Faraone: Currently the genetic data that we're talking about carry no implications for the treatment of ADHD. There is now an ongoing research program in my laboratory and other laboratories around the world to investigate what we call the pharmacogenetics of ADHD, to try to predict medication response from a person's genetic background. There is certainly some precedent for that in medicine. We know that genes control pharmacokinetics. The CYP 2D6 system, which is very well known to physicians, controls the metabolism and distribution of medications in the body, and that can have an effect on drug response. But we're actually trying to drill down much deeper to look at the genes that are involved in the pharmacodynamics of the drug that control the drug's efficacy effects or the drug's adverse effect response beyond pharmacokinetics. Do those genes actually predict outcome? That would be extremely important for ADHD, because in a day when we have many compounds to treat the disorder we have no way of saying to the physician where to start first. Pharmacogenetics could answer that, but it's still too soon.
Dr. Surman: Along those lines, there was a study presented at this year's APA meeting in which lisdexamfetamine is compared with mixed amphetamine salts in terms of the maximum concentration and time to maximum concentration achieved after dosing.[4] In small groups of individuals, they found more variability in maximum concentration and time to maximum concentration in the group that received extended release mixed amphetamine salts (MAS XR) than those who received lisdexamfetamine (LDX), a lysine-linked amphetamine agent. Along the lines of your comments in answer to the previous question, can you explain what causes the variability between individuals in terms of response to stimulant even though it's the same active ingredient?
Dr. Faraone: That's a good point. Here are 2 medications. The ingredient is not exactly the same. We have mixed amphetamine salts on one hand and the amphetamine in LDX or lisdexamfetamine on the other hand. But each is basically an amphetamine product. What's fascinating about those results is that during the past 5 years we've seen a lot of stimulant formulations, and physicians have become very familiar with the pharmacokinetic curves for different methylphenidate and amphetamine formulations. What they've never seen, behind those curves, is how variable the pharmacokinetics are from patient to patient. It has not been a subject of research or discussion. And, actually, no one patient has the ideal curve. Some people may peak earlier; some people may peak later. Some people may have 2 peaks with extended release formulations. Some people may have moderate peaks.
What was interesting about the LDX vs MAS XR study was that it was the first study to ask, what do we know about variability of pharmacokinetics between different medications and could that be relevant to the treatment of a disorder? The first answer in this initial study is that there are some clear differences; that lisdexamfetamine appears to be less variable in terms of the way the drug is metabolized and distributed in the circulatory system and then, we believe, in getting into the brain -- it is much less variable than MAS XR.[4] Could that have an effect in terms of how efficacious the medication is? It might very well.
I've been studying effect size of LDX. And our initial LDX study -- and this is still very preliminary because we've only conducted 1 LDX study so far in children -- shows that it has a much larger effect size than some of the other stimulants. Is that because of its different pharmacokinetics? I don't know for sure, and no one can know for sure yet, but that is something worthy of study. It may be that this new type of delivery system, this new prodrug formulation may be different in a way that reduces variability and therefore improves outcome.
Dr. Surman: Some other factors that have been explored in research presented at this year's APA meeting are race and gender. Specifically 1 study looked at the methylphenidate patch in boys and girls with attention deficit disorder and found that there was little difference actually in efficacy, it worked similarly in both boys and girls, but actually boys experienced slightly more adverse events than girls.[5] And in a similar kind of study looking at different subgroups in a secondary analysis of LDX, white and nonwhite children had very similar efficacy and tolerability.[6] Is there any reason to believe that there are neurobiologic differences in different groups of patients that clinicians should be aware of in terms of ADHD treatment response?
Dr. Faraone: Well, these studies are very interesting. They are among a series of studies that we've seen over the years that are trying to predict medication response. Basically those studies have not been too successful because, as you know, it's very difficult to predict medication response, whether according to clinical features, demographic features, gender, age, and so forth. So the good news from these studies is that we are looking at ADHD outcomes in different populations, and it's important that we're not just focusing on males; we're looking at females. We're not just focusing on whites; we're looking at nonwhites. We do know that the effects of the medication tend to generalize. They tend to work in almost every population studied, not simply the white males who used to be studied in the 1960s almost universally. That certainly has changed.
Why there may be differences in medication response gets us back to genetics. We know that genes do control a good deal of that response. We don't know exactly how in ADHD, so we can't use that information clinically yet. It needs to be explored. We do know, for example, that some differences in the brain may explain why some people will respond better to one medication or another.
I can give you a good example. It involves the pharmacogenetics of a mouse, but we have to start there because it's easier. I mentioned SNAP-25, a gene that's been implicated in ADHD. We first became interested in this gene because we have a mouse, the coloboma mouse, which is a model of ADHD; it is basically a very hyperactive mouse. This mouse has a deletion of chromosome 22, and in that deletion region it's missing one of the genes, it's missing a SNAP-25.[7] The investigator who studied that mouse found out that if you give that mouse a functioning SNAP-25 gene -- you basically can transgenically inject a working gene in it -- its ADHD goes away. Now this mouse is pretty interesting because when it's hyperactive, when it doesn't have the normal gene, when it's hyperactive and abnormal genetically, it will respond to amphetamine but not to methylphenidate. It's very specific. Methylphenidate does not help it.
Why is this interesting? It's interesting because SNAP-25 controls the vesicular machinery. This is the machinery that packages dopamine into little bubbles and let's those bubbles expel out into the synapse. Now we do know that amphetamine has the ability to literally, through reverse transport into the dopamine transporter, get into the intracellular fluid to pop the bubble, if you will, and to have the dopamine be released through the dopamine transporter by reverse transport. Methylphenidate doesn't do that. So what's fascinating is that the mouse responds to the medication that it should respond to. It responds to the medication that deals with the vesicular machinery. So whether we'll find this in humans, we don't know yet. That is ongoing to work, whether we can find specific neurobiologic mechanisms. I would predict that 20 years from now, certainly 50 years from now, we're not going to be talking about ADHD, we're going to be talking about a disruption of neural networks A, B, and C, that requires these kinds of medications for this kind of synaptic disorder.
Dr. Surman: So, people may respond selectively to different agents based upon the mechanisms involved.
Dr. Faraone: Exactly. And, hopefully, doctors will be able to use genetic testing, and perhaps neuroimaging, to predict who responds best to which medication. Having said that, I always have to warn people that there are a lot of charlatans who will try to sell you a neuroimaging test, or some day a genetic test, who say, "This is going to be useful in your clinical practice." It isn't useful right now. I don't expect it will be useful within 5 years or so, so be very cautious before you send your patients off to spend lots of money on those kinds of tests.
Dr. Surman: Many studies have suggested that there's a lot of overlap with other conditions, ADHD and comorbid conditions, in particular recently the National Comorbidity Survey showed a very high overlap with lots of different mental health disorders.[8] And some presentations at this year's American Psychiatric Association meeting are highlighting overlaps with substance abuse and bipolar disorder. What's the strongest evidence for disorders that are linked, perhaps neurobiologically or at least clinically?
Dr. Faraone: Well, the least controversial, most well known would be conduct disorder and learning disabilities. We have known since the 1960s, and no one argues, that these are comorbid with ADHD. It's very well accepted.
As you move up the controversy ladder, nowadays most people accept that depression and anxiety are common in ADHD in both children and adults. And most people wouldn't argue that substance abuse is also common in ADHD. These are very well validated, and anyone who would argue with that is not reading the scientific literature because it's certainly out there.
The biggest controversy nowadays has to do with bipolar disorder. The controversy centers around how one defines bipolar disorder in a pediatric population and then what does one do about it. That's raised a lot of controversy. When one talks about the comorbidity of bipolar with ADHD, there becomes another layer of controversy. That being said, many well-designed studies now show that if you take a group of ADHD children, an appreciable portion of them, around 15% or so, will have a very serious syndrome of psychopathology that frequently requires hospitalization, and shows the signs and symptoms of bipolar disorder as defined by DSM-IV.[9,10] One can argue whether it's bipolar disorder, but the main point is that they have those symptoms, and some of us, including myself, would say they meet criteria for bipolar disorder and we should conceptualize it that way. Others will argue that we should do something else. What physicians need to understand is that when you have to treat a patient, you can't get involved in semantic discussions of what to call something because everybody agrees that these kids exist and they have serious psychopathology.
Interestingly, you asked about what is the neurobiological basis for some of these comorbidities. We have conducted a lot of family studies, genetic studies, looking at comorbidity, and what we find is that these comorbidities tend to travel in families.[11-13] So it's not simply the child who has 2 disorders, ADHD plus bipolar; when we look at the relatives, the relatives also can have ADHD and bipolar disorder. They are at risk for both. It's very important for bipolar disorder because the bipolar disorder phenotype is -- or the bipolar disorder diagnosis I should say -- is very controversial among children, but not among adults. When we see the elevated risk among the parents of ADHD children, an elevated risk for bipolar disorder tells us that bipolar disorder in the child is probably likely. Interestingly we also see in the parents' comorbidity, that if they have bipolar disorder, they tend to also have ADHD. In studies looking at adults with bipolar, when there's no controversy with their diagnosis, if you do retrospective medical histories, psychiatric histories of these bipolar adults, what do you find? You find a high prevalence of childhood history of ADHD. So there is very good evidence for that.
But why would disorders be comorbid? Well, in some ways, I like to say, the brain is a fairly small place. If something is going wrong in the brain it's affecting multiple circuits of the brain and some of those circuits may be close together. For example, the circuits that connect the frontal lobes to the subcortical centers comprise about 5 subcortical frontal loops, and they're involved in cognition, emotion, all of the higher mental functions that are involved in functioning as human beings. Well, it's easy to understand how, if the dopamine transport is defective, it's going to be defective in all of those frontal subcortical structures; therefore, it will have an impact not only on the cognitive or motoric functions, it's also going to have an effect emotional functions. So it makes sense to think that the same etiological hit, so to speak, such as having a defective D4 dopamine receptor or defective dopamine transporter, can have some effects on mood and lead to bipolar disorder, but also have some effects on ADHD and lead to ADHD. So some people say, well, why do some people have one, some people have both? Well, maybe some people have one because most of their hits are in the ADHD part of the brain, but not in the mood disorder part of the brain. But they have these extra hits in the mood disorder part of the brain, so if they get any more, they're at higher risk. This is speculation. It's theory. But the main point is that there are actually good reasons to believe neurobiologically that the overlapping and common pathophysiologies in the brain account for comorbidity.
Dr. Surman: Another comorbidity that I certainly see in my patients is executive function difficulty. But some patients with attention deficit disorder seem to have more organizational problems than others, and even when you treat ADHD well, sometimes the organization challenges remain. What are your thoughts about a neurobiologic basis for why some individuals have executive function difficulties more than others with ADHD?
Dr. Faraone: What it comes down to is that these people have a pathophysiology -- we don't know exactly what it is -- but something about it differs from what the average ADHD person has. Now remember, we say average ADHD person. Roughly 30% of ADHD children and adults will have an executive function disorder,[14] so it's fairly common among patients with ADHD, although clearly not universal. The seat of the executive functions is in the frontal lobes of the brain. The frontal lobes control all of the higher mental functions but particularly those functions that require us to organize our life, to abstract information, to respond to complex stimuli. The current neurobiologic thinking is that the neural circuits that connect the subcortical centers with the frontal lobes and with the cerebellum, this route of neurocircuitry is all involved in ADHD. It's very likely that the kids with ADHD who have the executive function deficits have more of a pathophysiologic hit in the frontal lobes. That would be my theory. But there certainly could be a good neurobiologic explanation. Of course, this is ongoing work looking at these kinds of theories to see if they're correct.
Dr. Surman: One study in the APA meeting this year looked at the effect of atomoxetine on executive function as reported on a rating scale and found that treatment with this agent certainly resulted in organizational function improvement.[15] It seems that it's one of holy grails of ADHD research, that many of our patients can focus and stick with things, but if you ask them to plan and organize, they fall apart.
Dr. Faraone: It's absolutely a challenge. Probably the main unmet need in ADHD treatment is, how do we deal with these executive function deficits, how do we deal with learning disabilities? Frankly, the medications don't do a good enough job. They provide some efficacy. If you look at stimulant studies, atomoxetine studies, some modafinil studies, these medications do reduce executive function deficit to an extent. But when you look at the magnitude of the improvement in each of these studies it's relatively small. It's nothing like the effect of stimulants on behavior, hyperactivity, impulsivity, inattention. Executive function effects are small by comparison.
So at this point in time, if you have a patient with executive function deficits, the medications are probably not going to get them all the way along. If they need help organizing, particularly for adults, cognitive therapies are being developed. Some preliminary studies have looked at behavioral techniques that help adults keep themselves organized and function better in their real world.
Dr. Surman: We have so many powerful techniques for understanding the brain and it's biology, and genes now, from imaging to molecular biologic assays. What are things going to look like in a clinic in the future?
Dr. Faraone: I think the first thing to remember is that, the revolution in biologic psychiatry started long before your time. In the early 1970s, people started to think that maybe the brain was involved in psychiatric disorders, and over a period of years adult psychiatry came onboard with that for the most part. There are still some resisters in the hinterlands. Child psychiatry came to the party later, but over the past decade or 2 they've certainly been very highly participatory in this idea that the brain is an important organ when it comes to psychiatric disorders.
I think the first thing clinicians have to understand about the genetic neurobiologic data is that the data are convincing. The data are solid. There is no doubt that the brain is the locus of ADHD. So the old theories that it's the mother's fault or it's the teacher's fault or Americans are lazy and that's why we have ADHD, we really can't consider those any more. We can't pretend that those are serious theories about ADHD. This is not to say that parents aren't important or that teachers aren't important or that the environment is not important. As I mentioned, there are environmental influences for sure. But it's extremely important to know that the brain is impaired in this disorder. It's important for clinicians to understand that in some depth because they're the ones who have to talk to patients and parents about taking medication. Many parents say, why is my child taking medications because he can't attend at school? And you need to be able to say, well, you know, there's very good evidence from twin studies about how genes influence the disorder, there are neuroimaging studies that show us consistent evidence that the brain is different in ADHD children than in non-ADHD children, and therefore, medications for ADHD make sense. This is a biologic condition.
The neurobiologic theory of ADHD is very important from the point of educating patients and parents currently. In the future we hope we'll go beyond that. We certainly hope that genetic neuroimaging data will help us define subtypes of ADHD that are more responsive to treatment or more responsive to particular treatments so that doctors will no longer have to choose randomly which drug to start with. We may actually devise a very well thought out algorithm based on neurobiologic evidence. We hope that that data will perhaps help us diagnose children better and maybe solve some of these comorbidity confounds, such as when comorbidity is real and when it is an artifact. These unfortunately are in the future, and so I say "stay tuned."
Supported by an independent educational grant from Shire
