Sabrina Siegel here with a special series brought to you by the NEI podcast.

Stephen Stahl on the most controversial, novel, and exciting topics in psychopharmacology today.

Every 3 months we will address a different theme in psychopharmacology.

Each theme is split into 3 parts with 1 part released each month.

The next theme is on novel perspectives and treatment strategies for ADHD.

Steven Stahl on the role of serotonin in medications for ADHD, non-traditional approaches to treating ADHD, and what the future holds.

Let's listen in to part 1 of our theme, Shifting Focus, a novel perspective on attention deficit hyperactivity disorder.

Welcome to another podcast in the Psychopharmastology series.

Andrew Cutler, here today, of course, with the inimitable Dr.

And we're going to be talking today about a novel perspective on ADHD.

You know, Recently, we have learned a lot more about the neurobiology of ADHD.

evidently, according to you, so I'm doing great.

My son just took the SAT, so I guess that was on my mind.

What has been the traditional dogma of the neurobiology of ADHD?

Well, in the old days, it was paradoxical conceptualization.

Why would you want to give a stimulant to somebody to slow down?

Well, there was something wrong with the circuitry that somehow that more was better and yada yada.

And so if you think about it as a striatal issue, which is motor in the striatum of the brain, it doesn't make sense that increasing a stimulants maybe at that level is going to be as effective and may even be the wrong direction because you're already wired and going too fast anyway.

So it's really transferred in modern days to a problem in the prefrontal cortex and that maybe it's a neurodevelopmental problem in the way the cortex is organized that starts really early in childhood or birth even, and that sometimes you, quote, outgrow it, but often you don't.

So it's a neurodevelopmental abnormality of the prefrontal cortex.

So we think of it more as a top-down problem, I guess, and that has always been a paradox, a conundrum for a lot of people.

You take a hyperactive kid, you give them speed, potentially, and they calm down.

But I guess we can think of it as turning on the prefrontal cortex and allowing it to regulate or modulate the striatum better.

In the case of the motor, you're probably having top-down inhibition.

And same thing with impulses, you know, you have drives that are subcortical and if they're not being sort of ridden hard and put away wet, if you will, if you're a cowboy, I guess I'm thinking of riding horses today, but you know, it would inhibit it, then they're out of control.

Now the inattention and the cognitive stuff is a little differently and more sophisticated, but top-down control of motor impulsivity and other type of behavioral impulsivity, that's probably what's happening.

Well, as we know, the prefrontal cortex has different regions and probably has different circuitry.

We know, for instance, that the dorsolateral prefrontal cortex is involved probably with attention and executive function, and the ventromedial, for instance, is involved with emotional regulation, and then There's a circuit that's involved with motor activity and impulsivity.

But, you know, it really sounds like there's 3 important circuits here, so there should be 3 clusters of symptoms.

But Steve, last time I checked in the DSM, there's only 2 clusters of symptoms.

Yeah, but, you know, you can finesse that a little bit for example the orbital frontal cortex may be involved with Impulsivity and so right that's more emotional whereas the ventral medial prefrontal cortex may be involved with emotions that are less impulsive, but in fact may not even be so much in the ADHD realm but things like guilt and sadness and things like that.

And I always like the rap song, you know, 1 of our silly YouTube videos we once did for the D LPFC the dorsolateral prefrontal cortex and that's really where a lot of the money is for cognition it has to do with executive function And so when you're not actually problem solving well, it's called executive dysfunction.

Now, you could say that is actually something you, once you arrive in Washington, D.C., you end up getting executive dysfunction from having been elected to office, but that's a different type of executive dysfunction we're talking about.

The executive dysfunction that we're talking about here is 1 in which you can't hold enough information in your brain to operate on it to solve a problem.

And so it's sort of like your RAM memory, you know, you gotta load stuff up and operate on that, then you can figure the solutions inside that information.

People with ADHD can't hold that, they lose their focus, they are distracted, and things like that.

So there's also the anterior cingulate cortex can be involved a lot with Attention as well as at least exactly paying attention and holding attention and called selective attention But there's a funny thing about attention if you actually are too focused you don't actually switch attention when you should be and you basically are out of whack.

So basically, you're right, it's various types of connections between the various regions of the prefrontal cortex and the subcortical structures, each of them kind of mapping to a different symptom complex.

Yeah, you know, I've done a lot of work with ADHD, both clinically and lots of clinical trials, and what you're describing makes a lot of sense with the clinical presentation.

These people have a lot of trouble with working memory and sustained attention, but also executive function.

They don't have sometimes good self-monitoring, self-awareness, judgment.

They don't always consider the consequences of their actions.

So that really fits, Steve, clinically what's going on.

Well, many of us in today's world have to be able to multitask.

Now if we multitask to a fault, We actually pay no attention to anything and we don't get anything done But obviously it's true that you you know, your device goes off you're on the screen.

You're looking at that Maybe you're reading something and you may be thinking of more than 1 thing And so, you know multitasking is required in today's technical world.

And I find, you know, these people, they can orient, they can pay attention, they can orient to stimuli, but they can't sustain it.

It seems that they have interest-based focus rather than priority-based.

You know, someone who doesn't have ADHD can say, well, this is important.

But with ADHD, it's, well, this is important, but hey, look at that.

And then they procrastinate because they have no sense of time.

I think the 4 words that comprise the name of this condition are absolutely wrong, all 4 of them.

This is not attention deficit because if somebody's interested, they can lock in and hyper-focus and then they actually have trouble shifting attention.

You can have the predominantly inattentive presentation.

It's different ways of processing information.

You know, there's some things the ADHD brain does very well, and there's some situations ADHD brains thrive.

You get stuck in school when you're a kid.

Yes, and there's probably cognitive training, whether you even know that that's what you're doing, you learn how to overcome that.

types of effort that you can give will do that.

Also, I had a professor, Steve, who used to say IQ points can compensate for a lot.

And very often I find bright kids or kids who have a mom who can really compensate, they don't come to attention until much later.

Often when they're going off to college and then they have to organize for themselves and more cognitive demand and keep track of things and then the wheels fall

Absolutely, You end up seeing an explosion of ADHD diagnoses in freshman college.

This is 1 of the reasons DSM-5, a lot of us think DSM-5 didn't go far enough and didn't really evolve the criteria for ADHD enough based on what we now know, but at least 1 of the good things was in DSM-IV, Steve, you had to have symptoms before the age of 7, meaning 6 or below.

Well, how many adults can remember what they were like when they were a six-year-old, right?

Adam Back How many adults have a copy of their nursery school or kindergarten report cards lying around?

So, you know, so the good news is that the DSM-5 upped the cutoff point till the age of 12, symptoms before the age of 12.

And that actually makes a little sense because that's when middle school starts and now you start having to move from classroom to classroom, you have more homework, more cognitive demands, there's still people who think that sometimes someone can be compensated and may not have big problems, but the symptoms are usually there.

you know, if you're a little boy and you're crawling on the desk, you know, you're hyperactive.

So this used to be just called hyperactivity.

Those kids are running all over the place, usually boys, and they're usually young.

But like you say, some of the inattention, particularly if you have a lot of IQ points, isn't really uncovered until the extra effort and the extra intelligence is basically overcome by the cognitive load, if you want to call it that.

This was originally conceptualized, as you said, as a hyperactive disorder.

As a matter of fact, it was called at 1 time hyperkinetic reaction of childhood.

Now sadly, it was also called minimal brain damage or minimal brain dysfunction at 1 point.

And that really came out of 1 of the influenza pandemics where people who got influenza encephalitis or meningitis, they ended up looking like these hyperactive kids.

And so people thought, well, there must be some kind of brain damage that we just can't see here or some minimal form of brain damage.

But clearly, our understanding has evolved to incorporate inattention and some of the other associated symptoms.

And you know, you're right that in childhood, ADHD gets overdiagnosed in boys because they tend to be more hyperactive and get into trouble.

And then the inattentive girls are sitting in the back of the classroom spacing out, not causing trouble, and they end up coming to attention later, often in adulthood.

Well, 1 of the terrible misconceptions that you can talk about for girls is they get diagnosed as being blonde.

You know, spacey girls, and that, you know, and it isn't until they go to college when they really start to follow it back cognitively in performance that it's actually, Oh my god, this is ADHD, but this was not an impulsive nor a motor hyperactive person.

So a lot of girls are not diagnosed, hopefully less so today as people are aware of what we're talking about here, Because it comes in that flavor.

They're quiet, they don't bother anybody, they just can't get their homework done.

Now, I've seen some hyperactive girls too, so you can see it, but you're right, it's far more common in attention.

But, you know, if you think about it, Steve, who keeps track of the household?

Who makes sure that the husband and the kids go to the doctor and take care of things and all that tends to be the woman, I'll be honest, not always, but often it's a woman.

So if a woman is having trouble, Who reminds her of things?

Who keeps her in line and in track, right?

And with the COVID pandemic, now all of a sudden, you know, you have to, your kids are home from school, doing virtual school, and you've got, maybe you have a job and school.

I mean, the wheels fell off for a lot of people.

The fastest growing group of people being diagnosed now, Steve, is women, by the way, which is interesting.

And so, you know, the idea is there's something about the maturing of the prefrontal cortex, which is slower and maybe never quite normalizes, and that's really the dynamic.

It's not like minimal brain damage dysfunction.

There's no lesions you can see under the microscope, but it's thought that the circuits are inefficient in information processing.

There's a classic article by Philip Shaw and colleagues that demonstrates this.

They followed developing kids' brains, and they found that kids with ADHD, their cerebral cortex, especially the frontal part, is delayed by up to a year and a half in development compared to controls.

What's interesting is the area that developed faster on average was the motor strip, the primary motor strip.

And then the areas that have to do with intelligence, of course, we're right on target.

So you can be very intelligent and still have this condition.

Well, we've learned more about the neurobiology.

And well, let's first of all talk about again the dogma sort of is you know a lot of times in psychiatry it seems like we propose pathophysiology based on how our effective medicines are shown to work, right?

For years, depression was a serotonin problem, too little serotonin or something like that.

Well same here, all of the medicines that have been shown to be effective are increasing dopamine or norepinephrine function and so we understand there's got to be something wrong with dopamine and norepinephrine transmission, right?

Yeah, and it turns out that the prefrontal cortex is critically dependent upon the correct, if you will, tuning of norepinephrine and dopamine in what we would call the pyramidal neuron, which is 1 of the major captains of the circuit.

And so, if you don't have efficient use of that circuit, then you're either slow or it doesn't get done.

And it turns out that usually norepinephrine and or dopamine are too low.

Now, that's an overgeneralization, but it turns out that the way you tune the circuit is to increase those neurotransmitters.

And it's interesting because there's dopamine and norepinephrine increased, but in the cortex you don't actually increase dopamine by doing anything to a dopamine neuron directly.

You know, there's no dopamine transporters, really, in the prefrontal cortex to speak of.

So if you have something like a dopamine reuptake blocker, it doesn't do anything in the cortex because there's nothing to block.

Well, the answer is that, if you can believe it, the norepinephrine transporter not only transports norepinephrine, no duh, it also transports dopamine.

So the way that dopamine actually gets terminated in the cortex is that it's allowed to cruise away from the dopamine synapse in a puff in a cloud, sort of like in a cell phone radius, until it reaches an orphan efferent transporter, which then sucks it up like a vacuum cleaner and terminates its action.

If you block that transporter, you will enhance even further the actions of dopamine in the cortex.

So it's really norepinephrine transport inhibitors in the cortex that have a great deal to do with the enhancement of efficiency of information processing of both dopamine and norepinephrine just by hitting the norepinephrine transporter in ADHD.

So dopamine hitches a ride on the norepinephrine transporter in the prefrontal cortex.

But of course, in other parts of the brain, striatum, there are dopamine transporters.

The norepinephrine reuptake inhibitors aren't doing much then with dopamine in the striatum, and maybe that's why they don't seem to cause the same buzz, euphoria, high, you know, the

So that, you know, to tickle the norepinephrine transporters in the brain, because really amphetamines and stimulants are dual acting.

They act on both dopamine and norepinephrine transporters.

So how can this drug, which also in another form of methamphetamines, causing 1 of the worst epidemics of drug abuse in the country also be therapeutic.

Because to whack the heck out of the striatal dopamine receptors so that you have a euphoric trip or joy or abuse, you have to have much higher doses than you used to treat ADHD.

So, generally speaking, you're under the radar for that.

And so you get norepinephrine in the cortex, dopamine in the cortex, but you don't get a whole lot of dopamine in the striatum, which you maybe get enough for a little motivation, but not, hopefully, enough to actually be abused.

I mean, we know that methamphetamine, crystal methamphetamine is much more potent at releasing dopamine and that's why it's abused.

You know, something else is curious, Steve.

While both methylphenidate and amphetamine block the reuptake of norepinephrine and dopamine, isn't there a difference?

Amphetamine does something else, especially as you raise the dose.

the transporter around, it blocks Femad, you get release of dopamine.

And what's interesting is that that occurs when you really blast the dopamine neuron, as you say.

And What's interesting about that is that not only is the difference between a therapeutic use of these agents different from the abuse by dose, it's also by duration, because There's nothing greater to release dopamine, like you say, and open up those channels and not only block reuptake, but make spit all the dopamine, you know, like wring it out of that dopamine neuron fast, it's whack it real hard.

So Why do you think that oral amphetamine isn't abused as much as IV amphetamine isn't abused as much as smoking amphetamine or cocaine?

Because you can imagine if you laid out the surface area of your lung, it'd probably cover the whole wall in front of you.

That's how much surface area your lung has.

So when you smoke something, it goes into that, gets absorbed, and like a huge ram goes up your carotid artery and blasts your brain full of this reuptake integration, and that is a very different pharmacology.

It's mostly dopamine at that point, less sodium or epinephrine.

And then all of a sudden, a glorious cloud of dopamine comes out, which you're hoping to do with controlled release, which you're seeing more and more all the time, even at the low levels of dosing that we're seeing, there's a huge difference.

Amphetamine given in controlled release is much different than amphetamine given in immediate or even, you know, smoked.

So, it turns it into a different drug, and the drug we want is the controlled release, more neurodermatologic, less dopaminergic, more cortex, less striatum.

Yeah, And this is of course why Adderall immediate release for instance is the drug of choice.

You know, I've always noticed that on the street, you know, street value tells you a lot.

Addicts or connoisseurs, Adderall has a much higher street value than say Ritalin or methylphenidate.

And that's because of what we're talking about.

You get much more of a burst of dopamine, especially as you push that dose up higher.

It's going to be interesting to see what the listeners think about that because, you know, the dopamine of Adderall means, what if a patient comes in with no prior diagnosis and no history and is an adult and doesn't remember or won't tell you what happened earlier and wants immediate release Adderall as the first prescription when they come to your office?

Well, you know, I guess it's in the standard of care and it's in the treatment algorithms, but I would say no.

And so, because of what you say, is that the abuse, the liability, it's not even so much abuse, It's almost misuse and diversion, giving it to other people.

So it's not as much fun to take an immediate release stimulus because the glory of that whacking the transporter, you can't do it with a controlled release.

Well, I would say standard of care now, especially for adults, is extended release.

I would not give somebody immediate release in that scenario that you described.

Particularly if people come in asking for it by name, that's always a red flag.

But your right, there's concept of abuse, misuse, and diversion.

Those are the 3 things and they're slightly different.

But, you know, getting back to this difference between methylphenidate and amphetamine, they have those similarities.

They both block reuptake, but the amphetamine is more potent, basically.

While most patients will respond to either 1, there is preferential response.

of people will do better with 1 than the other.

They may need that potency of amphetamine or they may have trouble tolerating it because amphetamines are more likely to cause irritability, appetite suppression and insomnia.

So 1 of the points for our clinicians listening is, look, if you've tried methylphenidate after methylphenidate and you're not getting response, switch over to an amphetamine or vice versa.

So obviously, dopamine, norepinephrine, the prefrontal cortex by the way, loaded with D1 receptors, loaded with alpha 2A and alpha 2C receptors.

We do have a class of drugs, while we've been talking about reuptake inhibition, increasing the amount of norepinephrine dopamine, we do have a class of drugs, while we've been talking about reuptake inhibition, increasing the amount of norepinephrine doping, we do have a class of drugs, the alpha-2 agonists, that bind directly to those norepinephrine receptors, guanfacine and clonidine extended release in particular.

Rodgers Well, we're beginning to see that maybe those receptors have maybe a bit more to do with impulsivity and aggression and even agitation than they do with cognition per se.

1 of the things that we do see is when children particularly have some behavioral disorders, that's sometimes when you go to the guanfacine or the clonidine and target some of that.

And it turns out that other agents that play upon the Alpha-2 or even the Alpha-1 system to shut down some of that excessive norepinephrine is being used in agitation.

For example, there's an alpha-2 agonist called dexamethadomidine that is actually useful in the agitation of bipolar and schizophrenia being tested in Alzheimer's agitation now, and I'm wondering if it's been tested in ADHD, because it would seem like that might be useful, except it's a PRN med, and it's just a little tape that you put under your tongue, but it might be useful on that basis.

And then also, a drug like Brexpiprazole, which has alpha-1 antagonism, shutting down norepinephrine, has shown to be useful in the agitation of Alzheimer's disease, possibly getting an FDA approval in the next year.

So playing on the alpha receptor could actually improve agitation and aggression.

Maybe attention, but certainly agitation and aggression and impulsivity.

Well, it gets back to the idea we talked about earlier of top-down regulation.

You know, ADHD and Alzheimer's and schizophrenia and bipolar all have problems with top-down regulation and so then you get this overactive limbic system, if you will.

What's interesting, Steve, is the alpha-2 receptor is fascinating.

Alpha-2B does other things, but alpha-2A is postsynaptic.

Alpha-2C tends to be a presynaptic autoreceptor.

And where the lowering blood pressure comes from is the presynaptic alpha-2c, which in the locus ceruleus tones down norepinephrine release.

So that's exactly what we want to do for agitation.

Alpha-2a though, postsynaptically in the prefrontal cortex, Amy Arnst and colleagues at Yale have done a lot of work that you can actually strengthen the circuitry and maybe help cognition and executive functioning a little bit through actions at alpha 2a postsynaptically by stimulating that.

So, you know, it could be a tale of 2 cities here where you're helping a little bit of tension and then also the obviously the hyperactivity.

I find those drugs to be the best really for augmentation.

They're hard to tolerate due to sedation by themselves and so adding them to stimulants is a terrific combination like peanut butter and jelly.

Well, when you do that, seriously, are you looking for more pro-cognitive effects of the alpha-2 drugs, or are you looking for more behavioral impulsivity and agitation improvement with those drugs?

While the stimulant is in the bloodstream, it's the latter.

However, what's the problem with stimulants?

They take time to kick in in the morning and they have to wear off at night or the kid won't go to sleep so they're uncovered.

They help cover the bookend times and they do what you were talking about and sometimes they do allow you to get away with a little bit lower dose of a stimulant which may be a good thing.

Also you know their side effects are completely complementary.

I mean think about Stimulants raise blood pressure, the alpha-2s lower it.

Stimulants make you alert and have insomnia, the alpha-2s are sedating and so on.

Well see, there you've got your bad myth, Andy.

1 plus 1 equals 10 on therapeutic effects, and 1 plus 1 equals 0 on side effects.

So, you know, I was an investigator in these trials with the alpha-2s.

I'm an author on the paper of the extended-release guanfacine added to stimulants, and what we saw was less side effects when you combine these 2 drugs than either drug alone.

I guess that's an example of rational polypharmacy.

Of course, we are all too often see irrational polypharmacy.

But polypharmacy is not necessarily a bad word, Steve.

The fact is that it's done in all fields of medicine.

I mean, if you're treating hypertension or diabetes, it's not unusual to combine 2 different mechanisms.

Well, I think it has to do with sometimes using 2 benzodiazepines or 2 antipsychotics or 2 stimulants, and actually maybe not making a lot of sense just throwing drugs at people when you don't know what to do.

But you're right, co-therapy, which is synergistic mechanisms of action, you don't count the number of drugs you give, you count the number of mechanisms that you give.

And the other way to put it is that I just told you that these circuits are controlled by at least 2 neurotransmitters, dopamine and norepinephrine, so I joke and say, well, if God can commit polypharmacy, why can't we?

In other words, the natural thing in your brain is to have natural neurotransmitters more than 1.

And you could conceptualize that to put things right, you might need to play upon more than 1 of them to get maximal therapeutic outcome.

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NEI Podcast - E183 - The PsychopharmaStahlogy Show: Shifting Focus: A Novel Perspective on Attention Deficit Hyperactivity Disorder (ADHD)