Chapter 42: ADHD – Stimulant & Nonstimulant Drug Therapy

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Welcome to the Deep Dive.

Today we're jumping into a really common and important topic you'll definitely see in practice, attention deficit, hyperactivity disorder, or ADHD.

Yes, and specifically we're going to focus on the pharmacotherapeutics, pulling directly from Chapter 42 of the Advanced Practice textbook.

Exactly.

Our goal here is to really break down the treatment side, the drugs, how they work, why you'd choose one over another.

Think of this as a focused study aid, making those complex tables and guidelines feel more, you know, manageable.

Right.

This is for you, the advanced practice student or clinician.

We're focusing on the different indications for treating ADHD across different ages.

We want to unpack the why behind the choices.

Okay, so let's start with the basics, but from that clinical angle.

What exactly is ADHD at the neurobiological level?

What's going on?

Well, fundamentally, ADHD is seen as a cluster of behaviors linked to neurodevelopment.

Things like inattention, difficulty concentrating, forgetfulness and hyperactivity, or impulsivity, like not being able to sit still, interrupting people.

And these behaviors negatively impact whether it's school, work or social function.

And biologically, where's the issue?

The core issue seems to involve specific brain regions.

The prefrontal cortex, your executive function center, the caudate and the cerebellum.

We often see reduced volume or maybe more importantly reduced function in these areas.

The brain's command center, basically.

Pretty much.

And the key players in communication there are neurotransmitters, specifically dopamine, DA and norepinephrine, NE.

Now, here's the crucial bit for understanding treatment.

That prefrontal cortex works best under moderate levels of these catecholamines.

Okay.

Exactly.

If the levels are too low, you get ADHD symptoms.

But interestingly, if they're too high, you also get problems, often agitation or feeling overwhelmed.

So our whole pharmacologic game plan is about trying to gently nudge those DA and NE levels back into that optimal moderate zone.

Got it.

Finding that Goldilocks spot.

Okay, but before we even think about drugs, we need the diagnosis right.

What are the absolute must haves according to the DSM -5 criteria?

So the DSM -5 lays it out clearly.

You need a certain number of symptoms, six or more for kids, five if you're 17 or older.

These symptoms need to have been going on for at least six months, causing real problems in daily life.

And they have to be out of line with the person's developmental level.

Okay.

But here are the two points that often trip people up.

First, some of those symptoms must have been present before age 12.

And second, the symptoms need to show up in two or more settings like home and school or home and work.

That first one, symptoms before age 12, must be really tough to confirm sometimes, especially in adults.

Their memory might not be great, which could even be part of the ADHD itself, right?

Absolutely.

It's a major clinical hurdle.

You often rely on collateral information, talking to parents, digging up old school reports if possible.

But you also have to be super vigilant about comorbidities.

The overlap issue.

Yes.

Over two thirds of people with ADHD have at least one other condition, often anxiety or maybe a mood disorder.

And guess what?

Those also affect concentration and focus.

So you really have to tease out, is this primary ADHD or are these symptoms driven more by, say, underlying anxiety?

It's tricky.

Definitely sounds like it.

So, assuming we've nailed down the diagnosis, the guidelines, like from the AAP, you're nice to talk about a multimodal approach.

Can you walk us through the basic treatment algorithm?

Sure.

The first big branching point is age.

For the really little ones, ages four to five, the guidelines are clear.

First line is behavioral therapy, period.

No meds initially.

Not unless the symptoms are really severe and behavioral approaches haven't been enough.

If medication is needed, then it's usually methylphenidate.

But once kids hit school age, say six to 18, the recommendation changes.

Stimulant medication becomes first line, either alone or ideally combined with behavioral intervention.

And for adults.

For adults, after trying things like environmental changes or organizational strategies, drug therapy is typically first line, usually starting with either amphetamine salts or methylphenidate.

And the overall goal is always the same.

Get those core symptoms,

the inattention, hyperactivity, impulsivity under control while keeping side effects manageable.

Exactly.

Minimize the bad, maximize the good.

Okay.

That leads us perfectly into the first line drugs.

The stimulants.

Let's compare the two big players here, methylphenidate and amphetamine.

How do they actually work differently?

Let's maybe think about table 42 .2 from the text.

Right.

So both work by increasing those key neurotransmitters, DA and NE, in the synapse, but they do it slightly differently.

Methylphenidate primarily acts as a blocker.

It stops the reuptake of both DA and NE.

More stays available.

And amphetamine does that too, blocks reuptake, but it adds another punch.

It actually promotes the release of norepinephrine.

The text notes this with a double up arrow for NE effects.

So it's generally seen as having a bit more of a norepinephrine kick.

Interesting.

But the text also says that whether a patient is more inattentive or more hyperactive, doesn't really predict which drug type will work better for them.

That's a key clinical point.

You can't predict response based on the subtype of ADHD.

It's very individual.

And you need to remember that roughly 40 % of patients might only respond well to one of these types, not both.

So if methylphenidate doesn't work, then trying an amphetamine formulation is the logical next step and vice versa.

Don't give up after one fails.

Try the other class.

Got it.

Now, within these classes, we have immediate release, IR, and various extended options.

Why would anyone still use the old IR forms with that potential crash when it wears off now that we have longer acting ones?

Well, IR can be useful sometimes, maybe for very specific short periods, like just for homework time in the evening.

Or if someone really can't tolerate the side effects of a longer acting dose all day, it offers flexibility for short bursts.

But generally, ER is preferred.

Generally yes.

For smoother coverage, better compliance taking it once or maybe twice a day is easier.

The key thing with ER, though, is understanding how they release the medication.

They aren't all the same.

For example, Ritalin LA gives you two distinct peaks, 50 % of the dose pretty quickly than the other 50 % later.

That might be good if you need strong coverage in the morning and again later afternoon.

Compare that to Concerta.

It uses a special osmotic pump system.

Only 22 % comes out immediately.

And the rest, 78%, is released gradually over the day.

That gives a much smoother, more consistent level.

So you need to match the release profile to the patient's daily needs and symptom patterns.

That makes sense.

We also have to talk about the elephant in the room with stimulants, abuse potential.

Especially since ADHD often co -occurs with substance use disorders.

Is there anything pharmacologically that helps mitigate that risk?

Yes, and this is a really important development.

Lisdexamphetamine, the brand name is Vivance, is a prodrug, meaning the molecule itself isn't active.

It has to be broken down by enzymes in the gut, specifically in the red blood cells after absorption, to become active amphetamine.

You can't crush it or snort it to get a quick high because the activation step happens after it's absorbed systemically.

So that makes it much harder to misuse.

Exactly.

It offers a significant safety advantage, particularly if you're treating someone with a history of, or current, SUD.

It's a very useful tool in those cases.

Okay, and when starting any stimulant, what's the dosing strategy?

It's always start low, go slow, find the lowest effective dose.

You gradually increase it, maybe weekly, until you see the desired benefit or until side effects become problematic.

And a key thing to remember, unlike, say, antidepressants.

The effect is immediate.

Pretty much.

You'll usually see the effects, good or bad, on the very first day the correct dose is taken.

If it's tolerated but not working well enough, you just carefully increase the dose at the next interval.

Let's cover the big safety issues.

What are the absolute contraindications for stimulants?

When should you just not use them?

Okay, major red flags for all stimulants include any known structural cardiac disease, moderate to severe hypertension that's not well controlled, hyperthyroidism, or if the patient presents with marked anxiety or agitation already.

Glacoma is another one.

What about ticks?

That's listed as a specific contraindication or at least a strong warning for methylphenidate, as it can sometimes worsen HIT ticks or Tourette's syndrome.

And of course, a history of substance abuse is a big concern, though sometimes in adults if the ADHD is severe and the risk of relapse seems low, the benefit might outweigh that risk.

But it needs careful consideration.

VIVANCE helps here.

What about those common side effects that parents especially worry about, like appetite and growth?

Right.

The most common things you'll see, often transiently, are trouble sleeping, maybe some initial agitation or irritability, and definitely decreased appetite, which can lead to weight loss.

More serious, though less common, are cardiovascular effects, palpitations, increases in blood pressure, or heart rate.

And the growth question.

The chapter notes that growth retardation might be a concern, potentially more so with higher doses used consistently over long periods.

It's not fully settled science, but it's something to monitor.

So what do clinicians do about that?

One common strategy, particularly for kids, is using drug holidays.

Maybe stopping the medication on weekends, or over the summer break when school demands are less.

This allows appetite to return, potentially helps with catch -up growth, and it's also a good time to reassess if the medication is still truly needed at that dose.

Okay, that makes practical sense.

So what if stimulants just don't work, or the patient has one of those major contraindications like a serious heart issue or active substance Where do we go next?

Let's talk second line.

Atomoxetine.

Right, atomoxetine.

Brand name, Stratera.

This is often your go -to second line agent.

It's indicated when stimulants haven't worked after trying both classes, or if they're contraindicated, maybe due to cardiac problems, active SUD, where even Vyvanse feels too risky, or sometimes if the patient has significant anxiety or attacks alongside the ADHD.

And a big plus is...

It's not a controlled substance.

That simplifies prescribing and reduces concerns about diversion or abuse potential.

Okay, mechanistically it's different, right?

An SNRI.

Correct.

It's a selective norepinephrine reuptake inhibitor.

So it works primarily on the norepinephrine side of things, not so much dopamine directly, like the stimulants.

Now the text highlights a really key point about its metabolism, especially for advanced practice.

Something about CYP enzymes.

Yes, this is crucial.

Atomoxetine is heavily metabolized by the CYP2D6 enzyme.

So if you patient is a poor metabolizer of CYP2D6, or if they're taking another drug that strongly inhibits CYP2D6, common examples are antidepressants like peroxetine or fluoxetine.

You have to adjust the dose.

You have to be very cautious with titration.

The recommendation is to stick with the starting dose for maybe up to four weeks before considering an increase, because the drug will hang around much longer in those patients.

You could easily overshoot and cause side effects otherwise.

Also, if someone has significant liver problems, you need to cut the dose, often by 50%.

That's a really important clinical pearl.

And unlike stimulants, the effect isn't immediate, right?

And there are some warnings.

Correct.

Onset is usually within a week or two, but finding the optimal dose can take several weeks, two to four typically between adjustments.

And yes, there are FDA -boxed warnings.

One is about rare but serious liver injury, hepatotoxicity.

The other is about a potential small increase in suicidal thinking, particularly in children and adolescents, similar to warnings on some antidepressants.

And other contraindications.

Because it boosts norepinephrine, you absolutely cannot use it with MAO inhibitors that could cause a hypertensive crisis.

And it's contraindicated in narrow -angle glaucoma.

Okay, so that's second line.

What if Adamoxetine isn't right or doesn't work?

Let's move to the third line options, starting with the alpha agonists, guanfacine, and clonidine.

What's their niche?

These are interesting.

Their main role isn't really for the core inattentive symptoms of

They're used more for the behavioral aspects, things like aggression, significant impulsivity, sometimes insomnia related to ADHD or stimulant side effects, and they can also help with THUNSICS.

So more for managing specific, challenging behaviors than boosting focus.

Generally yes.

The chapter considers them less effective overall than stimulants for core ADHD symptoms.

How do they work?

And is there a difference between guanfacine, intunive, and clonidine cafe?

They are alpha -2 -edrenergic agonists.

They work postsynaptically in the prefrontal cortex, helping to kind of modulate activity there.

The main difference is selectivity and duration.

Guanfacine is more selective for the alpha -2A receptor subtype, which is thought to be more involved in PFC function, and it has a longer half -life, which often means guanfacine might be better tolerated, potentially less sedation, less dizziness compared to clonidine, which hits more alpha -2 subtypes.

What are the side effects, and how long do they take to work?

Common side effects are usually mild fatigue, drowsiness, maybe some dizziness, or a slight drop in blood pressure or heart rate.

You have to titrate them up slowly, usually over several weeks.

It can take about four weeks, sometimes longer, to see the full therapeutic effect.

And you need to caution patients about using other CNS depressants concurrently.

And the final third line agent mentioned is Bupropion, or Welbutrin.

This is off -label for ADHD, right?

What does it fit?

Yeah, it's primarily used off -label, mostly in adults.

It might be considered if someone can't tolerate stimulants, maybe has co -occurring depression, or Bupropion could treat both.

The guidelines from APNIs don't typically recommend it for primary ADHD treatment, though.

What's its advantage?

It works as a weak norepinephrine and dopamine reuptake inhibitor, so it hits the right neurotransmitters, theoretically.

And a big plus is that it's not associated with dependence or abuse.

But it comes with a really significant warning, a major contraindication.

Absolutely.

And this is critical.

Bupropion lowers the seizure threshold.

Meaning it can increase the risk of seizures.

Correct.

So it is strictly contraindicated, a definite no -go in anyone with a history of seizures.

It's also contraindicated in patients undergoing abrupt withdrawal from alcohol or benzodiazepines, as that also increases seizure risk.

That really limits its use in certain populations.

It also has CYP2D6 interactions to watch out for.

Okay, that's a lot of information on the different drug classes.

Let's try to tie it together with a quick case, similar to case study 2 in the chapter.

Imagine KL, a 28 -year -old adult.

She comes in with classic, inattentive ADHD symptoms impacting her work.

But her history includes active substance abuse, a past history of seizures, and significant generalized anxiety.

Where do you even start?

Well, this case really highlights how the safety profile dictates the choice.

Stimulants.

Generally contraindicated due to the active SUD, the risk is likely too high.

Bupropion.

Absolutely not.

That history of seizures makes it contraindicated because it lowers the seizure threshold.

Alpha agonists aren't really targeting her primary complaint, which sounds like inattention affecting work.

They're more for behavioral issues.

So while not strictly contraindicated, they're not the best fit for the core symptoms here.

Which leaves atomoxetine.

It becomes the clear first -line choice for KL, almost by elimination based on safety.

It has low abuse potential, it doesn't lower the seizure threshold, and some clinicians find it might even help a bit with coexisting anxiety, though that's more anecdotal.

So the complex history forces your hand directly to atomoxetine in this case.

Precisely.

Safety first.

Makes sense.

And once KL, or any patient, is on medication and stable, what does ongoing monitoring involve?

Monitoring is key, and it's not based on blood tests.

It's all about function and side effects.

Use rating scales, standardized ones, or just careful clinical interviewing to track improvement in those target symptoms.

Organization, focus, impulsivity, whatever the main issues were.

Initially, follow -up should be pretty frequent, maybe monthly, until you've got the dose optimized and things are stable.

Then you can usually space it out to every six or maybe 12 months for stable patients.

And every visit, you're assessing not just efficacy but also adverse effects, asking about sleep, appetite, mood changes, checking blood pressure and heart rate, and tracking height and weight on growth charts for kids.

Great.

So this has been a really thorough deep dive.

We covered the neurobiology that need for moderate catecholamines, worked through the age based treatment guidelines, and really got into the weeds of the four main drug classes.

The high efficacy stimulants in their various forms, and then the non -stimulant options like amoxetine, the alpha agnes, and bupropion, understanding their specific niches and safety profiles.

It really covers the landscape and it brings up, I think, a really important final point for you, the advanced practitioner listening.

Consider this.

We know stimulants, when chosen and dosed correctly, are highly effective.

The response rate is often cited as over 90 % across the two classes.

So if you have a patient who has had adequate trials, meaning good dose, enough time of both a methylphenidate based stimulant and an amphetamine based stimulant, and they've truly failed both,

what's the critical diagnostic step you must take next?

Ah, that's a fantastic question.

If the best tools we have aren't working despite good effort,

you're saying you have to seriously question the original diagnosis itself.

Exactly.

Before jumping to third line agents, if multiple first line treatments fail, your immediate next step should be to fundamentally reevaluate if ADHD is truly the primary diagnosis, or if perhaps a comorbidity is mimicking the symptoms or complicating the picture more than initially thought.

Revisit the diagnosis.

That's a crucial takeaway.

Thank you for joining us for this deep dive into ADHD pharmacotherapeutics based on Chapter 42.

We hope breaking this down helps you feel more confident managing these treatments.

We hope it was helpful.

See you next time.