Transcript edited for clarity

Hello, and welcome to the Carlat Psychiatry webinar, on choosing a stimulant formula. I’m Chris Aiken, the Editor-in-Chief of the Carlat Psychiatry Report and assistant professor at the NYU School of Medicine. I practice outpatient adult psychiatry and have no financial ties to this material. 

Learning Objectives:

After the webinar, clinicians should understand:

Isomers

1. The risks and benefits of dextro-- vs. levo-amphetamine

2. The risks and benefits of dex- vs. levo-methylphenidate

Modified Release Mechanisms

3. Key differences among modified release mechanisms

4. How to select the right isomer mix and modified release mechanism for your patient

 We’re going to cover a lot of ground in this webinar, but it really boils down to two topics: Which isomer mix should you choose, and which release mechanism is the best fit for your patient?

In our last webinar, Methylphenidate vs Amphetamine, we talked about the differences between the two major stimulants – amphetamines and methylphenidate – and came down with a verdict that favored the methylphenidates for safety and tolerability, and the amphetamines for efficacy. In particular, methylphenidate is less likely to worsen any underlying psychiatric disorders, has a slightly lower abuse liability, and is less likely to have neurotoxic effects on the brain. The verdict: Start with a trial of methylphenidate.

But which formulation should you start with? The list is daunting, so let’s break it down a bit, starting with the isomer mixes.

Each stimulant comes as two stereo-isomers, the dextro and levo isomers, which are mirror images of each other, but if you’ve ever tried to cut with the opposite-hand scissors, you know that mirror image shapes don’t act the same. 

And neither do mirror-image stimulants. The dex- is the more powerful of the two. For amphetamine, the dextro isomer is 2-4 times more power than the levo, while the levo lasts long and carries an additional risk of more cardiac side effects. Levo-amphetamine still has some efficacy, however, while levo-methylphenidate is practically inert. For methylphenidate, the dex- accounts for nearly all the drug’s potency. 

Let’s look closer at how these isomers are packaged in the methylphenidates

Methylphenidate began life as Ritalin in 1955, an instant release drug given three times a day, and it stayed that way until extended-release versions appeared on the market, first with Ritalin SR in 1987 followed soon after by Methylin ER and Metadate ER. These 3 use a waxy coating to delay the release, which increases the duration from around 4 hours to 6 hours, but their release is unreliable, causing inconsistent levels. Ritalin LA and Metadate CD came next, which offered a mix of instant release and delayed release beads. The next major advance came in 2001 with Concerta, which has a unique OROS delivery system that pumps the medication out at a steady rate.
 That was followed by variations in the mode of delivery – patch, liquid, chewable, orally dissolving – but these versions – all of which are brand only – don’t offer much advantage unless the patient has difficulty swallowing pills. And one of them adds an additional risk – Daytrana patch can rarely cause permanent skin discoloration.

Jornay is unique – this one is really a delayed release – the patient takes it at night and it is not absorbed until morning.

Finally, among the branded options are two that vary the onset and duration. Aptensio has a similar duration to Concerta – 12 hours – but starts working faster – in 30-60 minutes, whereas Concerta takes 1-2 hours to take effect. Think of it as “Pick up the tempo…. Aptensio.” And Adhansia breaks the record for the longest duration of the methylphenidates – lasting 13-16 hours – but a more cost-effective way to achieve that is to add an IR on to the end of the day with Concerta.

 That’s 14 versions of methylphenidate, and the other isomer mix in this category is 100% dexmethylphenidate, better known as Focalin, first released in 2002. Focalin also has an XR which lasts 8-12 hours, and – the newest edition – is Azstarys, which – similar to Vyvanse – is a prodrug version of dexmethylphenidate that is designed to prevent abuse of the stimulant. 

That was a lot of info, and I’ve gathered the stats in a table that you can print out for reference in the webinar notes. Here are the regular methylphenidates arranged with the generics on top, but if I had to choose only 2 to use in practice it would be . . . Concerta and the original SR. Concerta offers steady delivery over a long 12-hour duration of action at a generic price, so it’s a good fit for most patients. But why did I choose the waxy-coated, inconsistent delivery of methylphenidate SR? Well, if insurance doesn’t cover the med your patient may have to pay out of pocket, and this one is the most affordable of the XR options.

Let’s look at those top options in more detail. This graph compares Ritalin SR – the waxy coated release – to instant release – you see it’s about equal to twice a day dosing.

And here’s the same comparison for Concerta, which is equivalent to three times a day dosing. Notice at the start of the day Concerta follows the same line as instant release Ritalin, and that’s because it contains 22% instant release. The reason they built that in there is that it takes a few hours for the extended release – the other 78% - to come out.

Here’s how that looks in the pill. The 22% instant release is in the outer coating of the capsule and breaks down over an hour. Then the OROS pump begins to slowly releases the other 78% an hour later and continues that release through a 2^nd compartment in the afternoon for a total duration of 12 hours.

The steady release of the OROS pump gives Concerta a monophasic peak – compared to Ritalin LA which releases the medicine in two bursts – a biphasic peak.

These graphs compare the release of all the methylphenidate varieties, and you see most of them are monophasic except these 3: Ritalin LA and Focalin XR at the top which have the same graph, and the 16-hour Adhansia on the bottom. You may find in practice that some patients prefer the steadier levels of the monophasic, single peak mountains.

Turning to dexmethylphenidate/Focalin. Is there any reason to pick this option of methylphenidate? Remember, the dex isomer is responsible for all of methylphenidate’s therapeutic benefit, so if we’re going to take a stand against polypharmacy why not just get rid of the levo- isomer and simplify things?

But is there any measurable benefit when we do? You see here the dex-isomer peaks higher and faster when it’s given on its own, for some reason giving with levomethylphenidate pulls the levels down a bit. But this is not enough of an effect to have any clinically meaningful difference. In fact, there are a few head-to-head studies comparing methylphenidate with Focalin dexmethylphenidate, and there is not a discernable difference in their benefits or side effects.

So, without a strong reason to choose between the two, it probably comes down to the fact that there are many more options in the methylphenidate category – 14 – instead of the 3 to pick from with dex. And among these 3, 2 stand out as keepers – the extended-release Focalin, and the new Azstarys, because it has an abuse-deterrent mechanism much like Vyvanse, and I’ll cover those two together at the end of this webinar.

Let’s turn now to the amphetamines – things get a little more complicated here because we have 3 different isomer mixes.

First is the 50/50 mix of the two isomers – Evekeo, which was released in 2014, but that was actually a re-release. This medicine was the first stimulant to enter the market, branded as Benzedrine in 1935, and – much like Ritalin – it was marketed as an antidepressant for the first few decades of its existence. Benzedrine fell out of favor in the 1970s after a small controlled trial found that the two other stimulants on the market – dextroamphetamine (Dexedrine) and methylphenidate (Ritalin) – were more effective. And that’s what you’d expect, because Benzedrine or Evekeo is watered down with the less effective levo-isomer. So why use Evekeo? Well, it is generic now, and there was a small group of patients in that 1976 study that it did work better for – about 15% of them. If you use Evekeo, know that it is generic now and it does not come in an extended-release form because it doesn’t need to – the drug lasts 9-10 hours on its own.

Another stimulant that fell out of favor in the 1980s was Obetrol, which was marketed for obesity, but physicians stopped prescribing it when the FDA came out against using stimulants for weight loss because the risks are high and the benefits usually wear off after a few months. Obetrol was a 3:1 mixture of dextro and levo amphetamine. Sound familiar? Much as Benzedrine morphed into Evekeo, Obetrol was rebranded as Adderall in 1996. The XR version lasts 10-12 hours, and it marked a turning point in ADHD therapy in 2004 when it became the first stimulant approved for ADHD in adults, paving the way for ads like this one that emphasize work instead of school. The other 3 Adderall derivatives you see here are all branded – two of them offer different modes of delivery – ODT or liquid – and the last one, Mydayis, lasts 16 hours, as in “My Day Is 16 hours,” making it the Adhansia of the Adderall family with the same draw back that it’s cheaper to add an instant release on in the afternoon.

Finally, we have the pure, 100% dextroamphetamines, as instant release Dexedrine, extended-release Dexedrine spansules, and the abuse-deterrent prodrug Vyvanse.

Here I’ve summarized the specs you need to know to prescribe the amphetamines, and Adderall XR takes the prize as in this class for its practical 10- to 12-hour duration of action and generic price point. Adderall is the go-to amphetamine for many physicians, but that may be because this medication really created the market for amphetamines – as its name implies, which means “ADD for All.” But you might wonder why – when – compared to dextroamphetamine, Adderall has this levo-isomer hanging around that adds little to its benefits and increases its cardiac side effects. Why not just prescribe pure dextro-amphetamine?

And here there are two reasons to prefer pure dextro. If you caught the last webinar, you’ll recall some meta-analyses that found greater efficacy with amphetamines over methylphenidates, well most of that great efficacy came from the Vyvanse studies, and – the second reason – Vyvanse is abuse deterrent. The British recommend it over the other amphetamines for this reason, and I think we need to pay attention to that as the amphetamines have a long history of causing problems with abuse and diversion. So Vyvanse is one of my top picks, but until it goes generic – which may happen in 2023 – I’ll need to hang on to the low-cost Dexedrine spansules as a backup.

Let’s take a closer look at those top picks. Adderall XR, you see has a smooth monophasic peak, and doubles the duration of the instant release.

And here’s a myth you may have heard about Adderall. When Evekeo came out, you can imagine they had a hard time coming up with rationales for physicians to switch to the lower potency version of the drug. So they dug up this 2002 study, which suggests Adderall XR levels are significantly dampened by taking it with breakfast, while Evekeo is not affected by food. The problem was that this study was conducted by the makers of Concerta, who tried to use it to steal market share from Adderall XR back in 2002. And notice the graph cuts off after 8 hours, at 4pm. Most of these graphs cut off after 40-70 hours, so what they’ve done here is exaggerate a very small difference by magnifying the graph.

Here’s the pharmacokinetic graph as it’s normally presented. Can you see the difference that a high-fat breakfast makes? It’s there, see the red line, just not so impressive, and indeed not a difference that has made a dent in the clinical response in any studies.

I’ll end with two prodrugs. These have chemicals added to them that have to be cleaved off to activate them – take off the lis and you get dexamfetamine (trust me, that’s the same as dextroamphetamine – it’s just a British spelling). Take off the Ser and you get dexmethylphenidate. This mechanism has two advantages. First, it reduces the abuse liability because the medications can’t be injected or snorted – they are not activated that way. The second advantage is that the slow process of activating the drug effectively turns them into extended-release formulations without any extended-release coating. 

In the case of Vyvanse, the activation process occurs at a steady rate in the red blood cells, and my patients seem to appreciate that consistency – they report more ups and downs with other amphetamine formulations.

Here are those steady levels, with a 12–14-hour duration that’s about 2 hours longer than Adderall XR.

Azstarys is different from Vyvanse in 3 ways. First, is activated in the lower GI tract, not the blood stream. And its prodrug – serdexmethylphenidate – is actually a schedule IV stimulant – that’s a first – but you still can’t write refills for Azstarys because the drug contains 30% dexmethylphenidate which pulls it into the schedule II category. And that’s the third difference – Vyvanse doesn’t contain any regular dextroamphetamine.

Here are the three tablet sizes, which are supposedly equivalent to Focalin in these doses. Remember, when you convert from a prodrug to a regular stimulant you have to cut the dose down a bit because you won’t have that extra chemical adding weight to the dose.

But conversions are never perfect. This graph compares Azsarys with the supposedly equivalent dose of Focalin XR, but you see Focalin peaks much higher and comes down faster.

Another myth about Azstarys is that it lasts 13 hours, which I’ve seen in a few papers. This seems to be an innocent misunderstanding: The clinical study lasted 13 hours, but you see it stopped separating from placebo between 10-12 hours, which is about the same duration as Focalin XR.

You can’t snort or inject these prodrugs, but can you abuse them by taking them orally? That is certainly possible, but both of them produced lower levels of "drug liking" than their immediate release equivalents. The FDA recognizes this in its classification of ser-dexmethylphenidate – which is the only stimulant regulated as a schedule II drug – like the benzos are – but you still can’t write for refills on the brand Azstarys. It is still a schedule IV because it contains a little bit of regular dexmethylphenidate.

But what if insurance doesn’t cover these prodrugs? Then you’ll need to use the extended-release equivalents. I showed you the conversion from Azstarys to Focalin earlier, and here’s how you convert from Vyvanse to Dextroamphetamine: Divide the dose by 2.5, so that 70 mg of Vyvanse equals 30mg of dextroamphetamine. 

And here’s how the blood levels compare. The dashed line is crushed Dexedrine spansules – if you crush it it turns into an instant release which peaks high and lasts 4-6 hours. The red line is the XR spasules – they peak earlier than Vyvanse and phase out faster, lasting 6-10 hours instead of 12-14. But outside of the duration difference they both produce fairly similar levels. And when you prescribe ER Dexedrine spansules, you’re dipping into a bit of medical history, because this was actually the first extended-release drug - not just in psychiatry but in all of medicine, and it here’s how it all began. 

In 1949 the French pharmacologist Donald MacDonnell was shopping for groceries when he came upon a container of chocolate nonpareils. His first thought wasn’t about eating them. It was "Why not fill capsules with granules like these, and coat them with a medication that would dissolve at different intervals?" Three years later, Dexedrine Spansules came out.

It’s been 70 years since that discovery, and I thank you for joining me on this journey through the 30-odd formulations that followed.

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References

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Patrick KS et al, J Clin Psychopharmacol 2015;35(4):464-467

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Auiler JF et al, Curr Med Res Opin 2002;18(5):311-316

Tulloch SJ et al, Pharmacotherapy 2002;22(11):1405-1415

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