Bupropion and adult ADHD

[mistafab]

I would say that one issue I've had with bupropion for ADHD in someone with concomitant depression is that the jumps in doses based on available prescription strengths in my area make it hard to really calibrate for ADHD symptoms like you can with other meds.

With other meds, it's easier to attain the 'goldilocks' dose for ADHD.

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[whopper]

The problem with stimulants are cardiac and addiction risks.
The problem with non-stimulants are they usually don't work well except Qelbree. I've seen several patients where that worked tremendously well but then you got the problem that insurance often times won't pay for it. The other problem is Atomoxetine too has cardiac risks. I've seen several people think that cause it's a non-stimulant it's cardiac safe. No way. The FDA guidelines even recommend a cardiac evaluation at baseline.

 

[Atreides]

The FDA guidelines even recommend a cardiac evaluation at baseline.

I don't believe this is accurate. Unless there's red flags in family or patient history, there's no need for a baseline cardiac evaluation.

From the FDA:

"Children, adolescents, or adults who are being considered for treatment with atomoxetine should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation.

 

[aim-agm]

The problem with non-stimulants are they usually don't work well except Qelbree. I've seen several patients where that worked tremendously well but then you got the problem that insurance often times won't pay for it.

Do you have any idea why patients respond better to viloxazine than atomoxetine? It's surprising because the latter is ~30x more potent as an NRI. Any luck with desipramine efficacy when insurance won't cover viloxazine?

Tangentially, looking more into it despite being touted as an NDRI, bupropion does not have meaningful affinity for the norepinephrine transporter (Ki >10k), which is borne out by lack of effect on tyramine pressor response (Failure of bupropion to affect the response to tyramine in man.). That is, bupropion is just a weak DRI (Ki ~600) (and nicotinic antagonist). So, at least from an MoA standpoint, it would be valid to use an NRI+bupropion to treat ADHD. Has anyone had experience with this?

EDIT: The DAT selectivity of bupropion would further limit its efficacy, as NET can also transport dopamine which limits the effect of bupropion's already limited DAT blockade. Also, the prefrontal cortex doesn't have DAT and relies on NET for dopamine transport, so bupropion probably wouldn't do anything there.

 

[calvnandhobbs68]

The problem with stimulants are cardiac and addiction risks.
The problem with non-stimulants are they usually don't work well except Qelbree. I've seen several patients where that worked tremendously well but then you got the problem that insurance often times won't pay for it. The other problem is Atomoxetine too has cardiac risks. I've seen several people think that cause it's a non-stimulant it's cardiac safe. No way. The FDA guidelines even recommend a cardiac evaluation at baseline.

I don't believe this is accurate. Unless there's red flags in family or patient history, there's no need for a baseline cardiac evaluation.

From the FDA:

"Children, adolescents, or adults who are being considered for treatment with atomoxetine should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation.

Plus, like lots of package insert stuff, it's not even clear what the warning is based off of. You get these backend random adverse event reports that may or may not have anything to do with the med. You can see this by looking at the actual clinical trials...there were no cardiac adverse events in the child trials and "palpitations" reported in 3/540 in the adult trials over 18 and 25 weeks respectively. So we run into the perpetual problem with post-hoc reporting, if some kid with a structural heart disease starts strattera and then 6 months later has an arrhythmia or cardiac event, is that really from the strattera?

There have also been lots of attempts to look at actual cardiac risk from stimulants and strattera over the years and it's not particularly compelling in terms of supporting risk.

 

[clozareal]

The problem with stimulants are cardiac and addiction risks.
The problem with non-stimulants are they usually don't work well except Qelbree. I've seen several patients where that worked tremendously well but then you got the problem that insurance often times won't pay for it. The other problem is Atomoxetine too has cardiac risks. I've seen several people think that cause it's a non-stimulant it's cardiac safe. No way. The FDA guidelines even recommend a cardiac evaluation at baseline.

That's interesting that you mention this as I've also had better luck with Qelbree more recently too.

 

[Stagg737]

Do you have any idea why patients respond better to viloxazine than atomoxetine? It's surprising because the latter is ~30x more potent as an NRI. Any luck with desipramine efficacy when insurance won't cover viloxazine?

Tangentially, looking more into it despite being touted as an NDRI, bupropion does not have meaningful affinity for the norepinephrine transporter (Ki >10k), which is borne out by lack of effect on tyramine pressor response (Failure of bupropion to affect the response to tyramine in man.). That is, bupropion is just a weak DRI (Ki ~600) (and nicotinic antagonist). So, at least from an MoA standpoint, it would be valid to use an NRI+bupropion to treat ADHD. Has anyone had experience with this?

EDIT: The DAT selectivity of bupropion would further limit its efficacy, as NET can also transport dopamine which limits the effect of bupropion's already limited DAT blockade. Also, the prefrontal cortex doesn't have DAT and relies on NET for dopamine transport, so bupropion probably wouldn't do anything there.

Eh, not quite right with the bupropion. Wellbutrin's main active metabolite (hydroxybuprion, specifically the S,S enantiomer) is more potent at NET than at DAT and is more potent than bupropion as well as hydroxybupropion being present at a serum levels 5-10x in vitro than that of bupropion. If you significantly inhibit CYP2B6 then you can minimize or stop metabolism to hydroxybupropion and your point may be correct, but the time to build up enough hydroxybupropion in serum is part of why we believe Wellbutrin takes time to work.

I've also thought about studies combining atomoxetine with wellbutrin, but haven't found anything that was helpful. Would definitely need to be cautious about the combination d/t metabolic interactions with each other, but seems like it would have been studied at some point. I did find one retrospective analysis on combination therapy of any ADHD med, but the only thing I found specifically about Wellbutrin + atomoxetine was a Reddit thread, lol.

 

[docksan]

Do you have any idea why patients respond better to viloxazine than atomoxetine? It's surprising because the latter is ~30x more potent as an NRI. Any luck with desipramine efficacy when insurance won't cover viloxazine?

Viloxazine can be dosed once daily and spread like Depakote sprinkles, while Strattera cannot. It's also more easily absorbed in the body. I've had two patients on Qelbree so far who responded pretty quickly to it compared to Strattera with less sympathetic side effects overall. There's also the fact that Qelbree isn't generic yet.

There's the thought that maybe Qelbree even has some serotonergic modulation but don't quote me on that.

 

[aim-agm]

Eh, not quite right with the bupropion. Wellbutrin's main active metabolite (hydroxybuprion, specifically the S,S enantiomer) is more potent at NET than at DAT and is more potent than bupropion as well as hydroxybupropion being present at a serum levels 5-10x in vitro than that of bupropion. If you significantly inhibit CYP2B6 then you can minimize or stop metabolism to hydroxybupropion and your point may be correct, but the time to build up enough hydroxybupropion in serum is part of why we believe Wellbutrin takes time to work.

I've also thought about studies combining atomoxetine with wellbutrin, but haven't found anything that was helpful. Would definitely need to be cautious about the combination d/t metabolic interactions with each other, but seems like it would have been studied at some point. I did find one retrospective analysis on combination therapy of any ADHD med, but the only thing I found specifically about Wellbutrin + atomoxetine was a Reddit thread, lol.

My understanding is that hydroxybupropion is several times more potent that bupropion at NET. However, at minimum it would need to be ~100x better to have even minimal activity. The tyramine pressor study supports that hydroxybupropion is not a significant actor at NET, because the patients were on bupropion for a week (i.e. enough time for active metabolite to build up) and did not have any significant blunting of tyramine pressor response.

I think a study of a potent NRI+bupropion would be useful not just for potential ADHD treatment but also for testing the hypothesis that the clinical effect of bupropion is in part dependent on hydroxybupopion activity at NET and buildup of that metabolite. That is, if bupropion takes effect ~immediately when coadministered with an NRI (rather than taking time) it would be strong evidence for the hypothesis.

 

[Stagg737]

My understanding is that hydroxybupropion is several times more potent that bupropion at NET. However, at minimum it would need to be ~100x better to have even minimal activity. The tyramine pressor study supports that hydroxybupropion is not a significant actor at NET, because the patients were on bupropion for a week (i.e. enough time for active metabolite to build up) and did not have any significant blunting of tyramine pressor response.

I think a study of a potent NRI+bupropion would be useful not just for potential ADHD treatment but also for testing the hypothesis that the clinical effect of bupropion is in part dependent on hydroxybupopion activity at NET and buildup of that metabolite. That is, if bupropion takes effect ~immediately when coadministered with an NRI (rather than taking time) it would be strong evidence for the hypothesis.

Eh, again. I don't really buy that a tyramine pressor test/response is the best way to measure efficacy at the NET and is more related to interactions at the TYR30 receptor. Imo, the link between the two in terms of one being a reliable test for effects at the other is questionable. The below study suggested that duloxetine and venlafaxine even at higher doses are minimally noradrenergic, which generally goes against how we typically prescribe SNRIs (especially duloxetine). The article below also observed that all of this is assuming we believe the serotonin/monoamine hypothesis is correct, which we know is at best only a portion of the story.

Tricyclic antidepressant pharmacology and therapeutic drug interactions updated

New data on the pharmacology of tricyclic antidepressants (TCAs), their affinities for human cloned CNS receptors and their cytochrome P450 enzyme inhibition profiles, allow improved deductions concerning their effects and interactions and indicate which ...

www.ncbi.nlm.nih.gov

ETA: I would still be interested in seeing a study with bupropion + strong NRI as treatment for ADHD though. I actually proposed that a couple years ago in residency and was basically told "good luck" since no one really seemed interested.

 

[clozareal]

The problem with stimulants are cardiac and addiction risks.
The problem with non-stimulants are they usually don't work well except Qelbree. I've seen several patients where that worked tremendously well but then you got the problem that insurance often times won't pay for it. The other problem is Atomoxetine too has cardiac risks. I've seen several people think that cause it's a non-stimulant it's cardiac safe. No way. The FDA guidelines even recommend a cardiac evaluation at baseline.

I've been doing more of a deep dive into this. Qelbree doesn't seem like it's solely an NRI like Strattera despite being marketed as such and many of the effects are not only due to NET inhibition for which Qelbree is a moderate inhibitor of (vs Strattera that is a highly potent NET inhibitor). The biggest difference is in the serotonin effects of Qelbree over Strattera, which means it may be helping with mood and anxiety much more.

In the PFC, it increases levels of NE > DA > 5HT (but not glutamate, histamine, gaba, or acetylcholine). In the nucleus accumbens, it increases 5-HT > NE > DA.

New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties

Viloxazine was historically described as a norepinephrine reuptake inhibitor (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of ...

www.ncbi.nlm.nih.gov

The open label long-term extension adult data by Nasser show that Qelbree continues to decrease ADHD symptoms at each time point they measured up to one year at 400mg and at doses of 500-600mg, it separates out from 400mg.

Strattera has cardiovascular contraindications and warnings, which include sudden death, stroke, MI that Qelbree doesn't have. The QTc prolongation doesn't happen with Qelbree even at supratherapeutic doses. For Strattera, the QTc prolongation happens in 1.2% after 4 years of treatment.

 

[psycho-matic]

I have no idea why you would think that to be the case. Response to methylphenidate doesn't predict response to amphetamine. Both are in nearly all aspects superior to bupropion for this indication. Why would you try the least likely to work thing first when it isn't really any better tolerated?

Patients with substance abuse history, for starters

 

[psycho-matic]

The problem with stimulants are cardiac and addiction risks.
The problem with non-stimulants are they usually don't work well except Qelbree. I've seen several patients where that worked tremendously well but then you got the problem that insurance often times won't pay for it. The other problem is Atomoxetine too has cardiac risks. I've seen several people think that cause it's a non-stimulant it's cardiac safe. No way. The FDA guidelines even recommend a cardiac evaluation at baseline.

I've been doing more of a deep dive into this. Qelbree doesn't seem like it's solely an NRI like Strattera despite being marketed as such and many of the effects are not only due to NET inhibition for which Qelbree is a moderate inhibitor of (vs Strattera that is a highly potent NET inhibitor). The biggest difference is in the serotonin effects of Qelbree over Strattera, which means it may be helping with mood and anxiety much more.

In the PFC, it increases levels of NE > DA > 5HT (but not glutamate, histamine, gaba, or acetylcholine). In the nucleus accumbens, it increases 5-HT > NE > DA.

New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties

Viloxazine was historically described as a norepinephrine reuptake inhibitor (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of ...

www.ncbi.nlm.nih.gov

The open label long-term extension adult data by Nasser show that Qelbree continues to decrease ADHD symptoms at each time point they measured up to one year at 400mg and at doses of 500-600mg, it separates out from 400mg.

Strattera has cardiovascular contraindications and warnings, which include sudden death, stroke, MI that Qelbree doesn't have. The QTc prolongation doesn't happen with Qelbree even at supratherapeutic doses. For Strattera, the QTc prolongation happens in 1.2% after 4 years of treatment.

I wonder about a patient on Cymbalta for neuropathy if they could also take Qelbree

 

[clozareal]

I wonder about a patient on Cymbalta for neuropathy if they could also take Qelbree

Cymbalta is a major substrate of 1A2 and Qelbree is a potent inhibitor there. Don't combine.

 

[ObsequiousAplomb]

Patients with substance abuse history, for starters

Evidence is very clear - methylphenidate is superior to bupropion for both ADHD management and preventing methamphetamine use in patients with both MUD and ADHD. Avoiding the stimulant is probably doing those patients more of a disservice than it does satisfy your moralistic sadism.

 

[whopper]

Do you have any idea why patients respond better to viloxazine than atomoxetine? It's surprising because the latter is ~30x more potent as an NRI. Any luck with desipramine efficacy when insurance won't cover viloxazine?

No idea. The mechanism is about the same as Atomoxetine, but yet I've tried hundreds on Atomoxetine and never got a "this works great" patient. Only "this kind of works like 20% at best" type of patient. I've had plenty with Qelbree say it works great, about as well as a stimulant, and instead of weeks often times has noticeable benefit with days.

WTF is going on here I don't know.

Turns out any NRI reduces pain just that Duloxetine got the FDA approval. Studies where these were studied didn't show superiority with one vs another although like I'm sure most people here have seen, patients will report one worked better for them. Why? Cause the studies show that how any med works in 1 person could be different in another.

 

[calvnandhobbs68]

Strattera has cardiovascular contraindications and warnings, which include sudden death, stroke, MI that Qelbree doesn't have. The QTc prolongation doesn't happen with Qelbree even at supratherapeutic doses. For Strattera, the QTc prolongation happens in 1.2% after 4 years of treatment.

Where is this data from?

 

[whopper]

I'd had several patients try Atomoxetine and within days develop serious tachycardia. I'm talking over 150 BPM at rest. The problem here is via outpatient several patients, even when directed, won't check their heart rate and will only contact me if the HR is seriously noticeable such as uncomfortable palpitations.

I've tried Atomoxetine in forensic units because I could tell the patient had ADHD but didn't want to medicate them with a stimulant. Only there did I feel safe giving it out cause vitals were checked multiple times a day. It's not that the medication is dangerous, but it's in that zone where if you don't check it, some will slip through that were avoidable. Per the FDA guidelines 3% cardiac side effects.

I still see pharmacists and MDs saying there's no cardiac risks with Atomoxetine.

I've been doing more of a deep dive into this. Qelbree doesn't seem like it's solely an NRI like Strattera despite being marketed as such and many of the effects are not only due to NET inhibition for which Qelbree is a moderate inhibitor of (vs Strattera that is a highly potent NET inhibitor). The biggest difference is in the serotonin effects of Qelbree over Strattera, which means it may be helping with mood and anxiety much more.

Qelbree is approved in the EU for depression. I've noticed several ADHD patients taking it and their depression gets better, but the problem here is treating ADHD effectively often times improves depression because depression is often times caused by moderate or worse ADHD. I haven't reviewed the EU data but since the EU does have decent standards I would assume that Qelbree can treat depression even in those without ADHD. Due to the medication not having great insurance coverage with what it's already approved for in the USA-ADHD, I haven't given it out for only depression.

The biggest darned shame is I often times see elderly patients with severe ADHD and I don't want to give them a stimulant cause of the cardiac risks, and along comes Qelbree, we try it, it works brilliantly but then Medicare won't cover it and it's darned expensive so they don't end up taking it past the samples.

 

[psycho-matic]

Evidence is very clear - methylphenidate is superior to bupropion for both ADHD management and preventing methamphetamine use in patients with both MUD and ADHD. Avoiding the stimulant is probably doing those patients more of a disservice than it does satisfy your moralistic sadism.

You don't know me, so let's leave the personal insults out of this. It has nothing to do with morality. It's how I was trained. It has to do with risk, liability and protecting the patient from the consequences that could come with stimulant abuse. Of course people with a SUD can be on a stimulant but it must be done cautiously. I think it's reasonable to try a non-stimulant first in this population. Less abuse potential. If there's data suggesting the benefit is greater than the risk of using stimulants as a first line agent in those with a SUD, I'm open to looking at it.

 

[calvnandhobbs68]

I'd had several patients try Atomoxetine and within days develop serious tachycardia. I'm talking over 150 BPM at rest. The problem here is via outpatient several patients, even when directed, won't check their heart rate and will only contact me if the HR is seriously noticeable such as uncomfortable palpitations.

I've tried Atomoxetine in forensic units because I could tell the patient had ADHD but didn't want to medicate them with a stimulant. Only there did I feel safe giving it out cause vitals were checked multiple times a day. It's not that the medication is dangerous, but it's in that zone where if you don't check it, some will slip through that were avoidable. Per the FDA guidelines 3% cardiac side effects.

I still see pharmacists and MDs saying there's no cardiac risks with Atomoxetine.

You keep saying all this cardiac stuff. Where is the 3% number coming from? Do you mean the 3/540 adults who reported "palpitations"?

https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021411s035lbl.pdf

It's not as significant as you guys make it out to be. As I noted above, it's not even clear where this idea is coming from outside of random aftermarket reports. The clinical trials did not indicate this up to 25 weeks in adults.

 

[clozareal]

Where is this data from?

This is my go to for side effects of atomoxetine. Again, caveat in my CAP patient population.

https://www.jaacap.org/article/S0890-8567(09)60011-3/fulltext

 

[whopper]

Where is the 3% number coming from? Do you mean the 3/540 adults who reported "palpitations"?

From Medscape. They get their data directly from the FDA. From my own experience it does seem more like 3%.

 

[calvnandhobbs68]

This is my go to for side effects of atomoxetine. Again, caveat in my CAP patient population.

https://www.jaacap.org/article/S0890-8567(09)60011-3/fulltext

Okay so no control group and the mean change was nonsignificant, so shouldn't you counsel patients that they're just as likely to have a decrease in QTc interval as an increase?

 

[clozareal]

Okay so no control group and the mean change was nonsignificant, so shouldn't you counsel patients that they're just as likely to have a decrease in QTc interval as an increase?

I don't typically counsel patients on CV effects with Strattera other than increased heart rate and blood pressure, but I monitor that just as I would any other stimulant treatment. I often have already screened them for a family history of CV disease such as prolonged QT syndrome, sudden cardiac death, structural or arryhtmic heart abnormalities, unexplained fainting, etc.

CORRECTION: The mean change in QTc is nonsignificant after 4 years but it does go up slightly within those 3-4 years, but not above 500 msec to which I would be more concerned.

 

[aim-agm]

I've been doing more of a deep dive into this. Qelbree doesn't seem like it's solely an NRI like Strattera despite being marketed as such and many of the effects are not only due to NET inhibition for which Qelbree is a moderate inhibitor of (vs Strattera that is a highly potent NET inhibitor). The biggest difference is in the serotonin effects of Qelbree over Strattera, which means it may be helping with mood and anxiety much more.

In the PFC, it increases levels of NE > DA > 5HT (but not glutamate, histamine, gaba, or acetylcholine). In the nucleus accumbens, it increases 5-HT > NE > DA.

New Insights into the Mechanism of Action of Viloxazine: Serotonin and Norepinephrine Modulating Properties

Viloxazine was historically described as a norepinephrine reuptake inhibitor (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of ...

www.ncbi.nlm.nih.gov

The open label long-term extension adult data by Nasser show that Qelbree continues to decrease ADHD symptoms at each time point they measured up to one year at 400mg and at doses of 500-600mg, it separates out from 400mg.

Interesting, although very much a hypothesis and, of course, in rats not people. An issue with their hypothesis is that they believe it has to do with viloxazines very weak 5-HT2B and 5-HT2C antagonism (Ki 3900 and 6400 nM, respectively), but trazodone is a much better antagonist at those receptors (~100 and ~200 nM, respectively) and I'm not aware of any remarkable benefits trazodone has for ADHD.

 

[FlowRate]

An interesting perspective from Ghaemi (a refined version of which was published in Psychiatric Times this month.)

He's a little imprecise about how he uses the phrase "adult add" but he's mostly using it to refer to adults newly diagnosed with ADHD (meaning supposed childhood sx included.)