Auvelity, stuff not in the textbooks

[whopper]

I've been using it now on patients for months with shockingly good results. The manufacturer alleges 70-80% efficacy with 70-80% going into complete remission with benefits possibly starting day 1. I've seen this happen in front of my eyes with patients taking it and literally 1-2 hours later feeling tremendously better from even severe depression.

I'm posting here because several doctors will not prescribe a brand new med because there may be October surprises with the med with it being so new. I'm posting to start a discussion and to get people more experienced more quickly with this medication.

What I used to like to emphasize when I was a professor was what is useful in clinical practice that's not in the textbooks. Here's what I want to point out.
1-Likely not covered by insurance and IT'S EXPENSIVE.
2-If taken higher than FDA recommended dosages high likelihood of a seizure.
3-If the patient cannot afford the medication, but wants to be on it can they mix Bupropion along with OTC Dextromethorphan?

I'm not finished writing about this but will post this for now because I'm off and on the computer today.

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[allantois]

I find that it works surprisingly well too. Coverage is a concern as it is a 1k a month med if taken bid..

 

[TexasPhysician]

I’ve tried it about 10x, which I admit isn’t a lot. 4 are doing well. 6 couldn’t tolerate the first week on 1 pill. It seems very hit or miss.

 

[brainmedicine]

Can someone elaborate on the mechanism of action?

 

[PsyDr]

Can someone elaborate on the mechanism of action?

Its tussin is an nmda antagonist, that clears quickly. Bupropion inhibits 2D6, making the nmda receptor antagonism last longer.

 

[birchswing]

Its tussin is an nmda antagonist, that clears quickly. Bupropion inhibits 2D6, making the nmda receptor antagonism last longer.

<not a doctor or medical student>

That would make it like Nuedexta which uses quinidine for the same effect. Looking this med up, it looks like the bupropion is present in a dose that could be therapeutic on its own, whereas in Nuedexta, quinidine functions solely for enzyme inhibition to potentiate dextromethorphan.

 

[whopper]

Point #3 from my first post.
When patients can't afford this medication and they've already tried several other meds with no success the question comes up-should I prescribe them Bupropion 100 mg daily and they take it with OTC Dextromethorphan 30 to 45 mg?

This is a very difficult grey area.
Some patients NO!!!!: First some patients, even when educated on the mechanism and that they have to take it together, won't follow your instructions. Some people just aren't bright enough, motivated enough or lack enough cognitive reliability to follow directions on the order of a recipe. Some patients can't even follow your instructions when the only thing they're supposed to do it take 1 pill a day. BEFORE ANY OF YOU OVERLY SENSITIVE PEOPLE GET MAD, REAL CLINICIANS KNOW WHAT I'M TALKING ABOUT AND KNOW THIS IS TRUE.

What's the downside? Possibly death. Why? Bupropion is the only post 1980 antidepressant that reduces seizure thresholds to degrees where a less than monthly dosage all at once can cause a seizure. SSRIs and SNRIs, even if used all at once, a 30 day supply only causes uncomfortable serotonergic syndrome.

Potentiating the effect is it's Bupropion mixed with DXM-another medication that increases the effect of the other med because they're both metabolized by the same enzyme.

So on the one hand you got (and this is a real case of mine) patient who was so suicidal that he tried to hang himself, tried 3 SSRIs, 2 SNRIs, Buspirone, Mirtazapine, Fetzima, Trazodone, all at max dosages with hardly any benefit, and lo and behold of Auvelity and Vraylar his PHQ-9 went from >20 to less than 5 in literally less than a week.

And on the other hand I have another treatment-resistant patient, this one too attempted suicide, this one too is extremely treatment resistant, and Auvelity got his depression from with a PHQ-9>20 to less than 5, and the idiot decides to take 6 in one day cause he wanted to see "what would happen, maybe I'd get high" and he has a seizure, and is in the ICU for a few days WTF.

So, the point is you teach patients to mix Bupropion and DXM together you are giving them the ability to hack their meds to the point where they are now introduced to a new range of potentially stupid options. Some of whom will make the stupid mistakes before they realized you were right assuming they survived.
When I'm willing to teach patients to mix Bupropion and OTX DXM:
1) If Auvelity samples worked well on the patient...
2) If the patient was otherwise treatment resistant, you tried SEVERAL other meds without anywhere near as much benefit, and...
3) You explained to them (AND DOCUMENTED) you are only doing this cause they can't otherwise afford a medication that pretty much IS THE ONLY ONE THAT SIGNIFICANTLY HELPED THEM, yes I would teach them to mix the two meds together......
4) While telling the patient and documenting they better not PHUKING MESS WITH THE DOSAGES OF MY RECOMMENDATIONS WITHOUT CONSULTING ME. (For all of you people offended that I used the word "phuking," that word is being used out of respect to Phucket, Thailand, So I am now offended that you are offended because of your own cultural ignorance and counter your demand for an apology with a demand that you must apologize to the most humble, enlightened, and harmonious people of Thailand you racist, ignorant person . Just an apology won't do. You must now bow to a Buddha statue or you are now a racist!). (and for all of you who say I can't make a joke including Asian culture, I am Asian, so I am culturally certified to do so while pointing the finger at you for being culturally appropriating!)
In all seriousness, my sarcastic remarks are meant to keep me awake, although I am finding this hypersensitivity thing these days annoying.

And this brings me onto another clinical discovery.

DXM with other 2D6 antidepressants: What about people where they've had bad reactions to Bupropion, but are eager to try this new med? What's happened? Not surprising-same bad reaction, but guess what? "Doc, yeah the same bad reaction happened, but my depression got better in like an hour. I was so conflicted. I need to get out of this depression."

So I thought about it. The mechanism of this med is they're both metabolized by the 2D6 enzyme. What if I replaced the 2D6 enzyme with another antidepressant metabolized by the 2D6 enzyme? What are those antidepressants? Trintellix or Vilazodone will do.

So I had 2 of these patients stop Auvelity, and told them to buy OTC DXM, and try it with Vilazodone, or Trintellix. One each did these attempts. Both had tremendous success-like you'd expect with Auvelity with quick benefit but without the Bupropion side effects.

 

[allantois]

I actually think that they should have mixed DXM with something else - I have plenty of patients who couldn't tolerate bupropion, or have a hx of seizures

 

[whopper]

I’ve tried it about 10x, which I admit isn’t a lot. 4 are doing well. 6 couldn’t tolerate the first week on 1 pill. It seems very hit or miss.

Hit or miss which based on studies, and my own experience has been hit or miss determinable within days at 70%-80% efficacy with 1 possible step up in 3 days is a hell of a lot better than hit or miss with 50% efficacy that takes weeks to see if it works with tremendous step with up to 4 steps up
-1 step per week.
Further if Auvelity is tried, SSRIs were probably already tried. The science is now solid that some people just won't respond to SSRIs or SNRIs, making Auvelity an attractive alternative than trying yet another SSRI or SNRI where the science is strong it's doomed for failure that will take weeks of suffering to determine.

Agree the tolerability is a factor. As I said, the patient is stupid enough to play doctor and take 5 pills at once they're going to have a seizure. This type of patient is not an unfortunate 1 in a million, but more like on the order of 5-10%. SSRIs and SNRIs we could rest assured the patient was stupid enough to do something like that they'd only get serotonergic syndrome. I tell patients if they get a side effect from the starting dose of 1 pill a day to stop and either forget the medication or retry it at half a pill a day. Also I tell patient who are improving on 1 pill a day don't raise it to twice daily unless they could tolerate the 1 pill a day very well.

 

[whopper]

I actually think that they should have mixed DXM with something else - I have plenty of patients who couldn't tolerate bupropion, or have a hx of seizures

Agree but turn back the clock and read the original article in the Green Journal that introduced this novel approach.

Psychiatry Online

ajp.psychiatryonline.org

At the time Trintellix, and as of now it's still a tradename med so the company couldn't use that one. At the time Vilazodone was tradename, and while its currently generic, at the time of the applications for this med to the FDA they couldn't use it as they didn't own Vilazodone.

So that leaves Bupropion and a few other SSRIs or SNRIs, and the latter meds will then kill the med's commercial attractiveness with sexual side effects.

 

[calvnandhobbs68]

Whopper dude your pharmacology is all jacked up.

What's the downside? Possibly death. Why? Bupropion is the only post 1980 antidepressant that reduces seizure thresholds to degrees where a less than monthly dosage all at once can cause a seizure. SSRIs and SNRIs, even if used all at once, a 30 day supply only causes uncomfortable serotonergic syndrome.

Potentiating the effect is it's Bupropion mixed with DXM-another medication that increases the effect of the other med because they're both metabolized by the same enzyme.

No, the MOA is NOT that Wellbutrin and Dextromethorphan are "metabolized by the same enzyme".

Wellbutrin is a CYP2D6 inhibitor. Wellbutrin is metabolized by CYP2B6 and 2C19 (way less).

Dextromethorphan is a nothing inhibitor. Dextromethorphan is metabolized by CYP2D6 and 3A4.

DXM with other 2D6 antidepressants: What about people where they've had bad reactions to Bupropion, but are eager to try this new med? What's happened? Not surprising-same bad reaction, but guess what? "Doc, yeah the same bad reaction happened, but my depression got better in like an hour. I was so conflicted. I need to get out of this depression."

So I thought about it. The mechanism of this med is they're both metabolized by the 2D6 enzyme. What if I replaced the 2D6 enzyme with another antidepressant metabolized by the 2D6 enzyme? What are those antidepressants? Trintellix or Vilazodone will do.

So I had 2 of these patients stop Auvelity, and told them to buy OTC DXM, and try it with Vilazodone, or Trintellix. One each did these attempts. Both had tremendous success-like you'd expect with Auvelity with quick benefit but without the Bupropion side effects.

This makes no sense because (straight from the FDA packaging):

Vilazodone: "Coadministration of VIIBRYD with substrates for CYP1A2, CYP2C9, CYP3A4, or CYP2D6 is unlikely to result in clinically significant changes in the concentrationsof the CYP substrates"

Trintellix: "Vortioxetine and its metabolite(s) are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9,CYP2C19, CYP2D6, CYP2E1, CYP3A4/5"

Trintellix has literally been tested WITH dextromethorphan with "no dose adjustment" recommended (see Figure 4). Vortioxetine: Clinical Pharmacokinetics and Drug Interactions

You're seeing a bunch of placebo effect here bud. Give it with something that's an actual CYP2D6 inhibitor like Prozac or even cymbalta.

 

[whopper]

No, the MOA is NOT that Wellbutrin and Dextromethorphan are "metabolized by the same enzyme".

You are correct. I'm tying too fast an in a manner that the efficiency of the speed led to a mangle of words, but there is the same enzyme at play that's the major factor.

You're seeing a bunch of placebo effect here bud. Give it with something that's an actual CYP2D6 inhibitor like Prozac.

Fluoxetine? That's a great idea!

Placebo effect? Maybe-I'll have to re-examine the Trintellix and Vilazodone cases, but good thing to point it out. This is the entire reason why I'm throwing this out of the box stuff on this thread. I need my colleagues to parse out what I could be doing wrong and doing better. MY pharmacology is "jacked up?" Thank you! That's why I want your expert opinion no sarcasm, and only gratitude for your insight.

 

[allantois]

Also what should we make of those who abuse DXM?

 

[Celexa]

There was that recent trial of memantine for skin picking and trichotillomania with decent results. Consequently, I have started using memantine for that indication with some success.

Memantine is cheap, well tolerated NMDA receptor antagonist. Is there actually a reason to mess around with Auvelity with its costs and the risks of two meds before trying memantine? Genuine question.

Rotating with toxicologists gave me a whole new appreciation of the risks of bupropion and seizure which whopper lays out above. It is hard for me to be enthused by a drug that puts two potentially abusable meds together with a narrow therapeutic index.

 

[allantois]

Ketamine is also an NMDA antagonist, I suspect that as with SSRIs, the NMDA antagonists would still show some variation from one to another in their receptor affinities as well as efficacy

 

[Celexa]

Ketamine is also an NMDA antagonist, I suspect that as with SSRIs, the NMDA antagonists would still show some variation from one to another in their receptor affinities as well as efficacy

Right, no disagreement on that to be sure, but more on a practical level, if we have a safe and cheap drug with the same basic mechanism, is there a reason to not try that before the new, expensive, objectively riskier option? No drug company is going to start pushing memantine when it's cheap and off patent.

 

[allantois]

Right, no disagreement on that to be sure, but more on a practical level, if we have a safe and cheap drug with the same basic mechanism, is there a reason to not try that before the new, expensive, objectively riskier option? No drug company is going to start pushing memantine when it's cheap and off patent.

They just gotta mix it with some other generic and voila 1k a month lol

 

[Attending1985]

I haven’t used it yet and haven’t read too much about it. Is it recommended to taper other medications before starting it?

 

[shoomer]

There was that recent trial of memantine for skin picking and trichotillomania with decent results. Consequently, I have started using memantine for that indication with some success.

Memantine is cheap, well tolerated NMDA receptor antagonist. Is there actually a reason to mess around with Auvelity with its costs and the risks of two meds before trying memantine? Genuine question.

Rotating with toxicologists gave me a whole new appreciation of the risks of bupropion and seizure which whopper lays out above. It is hard for me to be enthused by a drug that puts two potentially abusable meds together with a narrow therapeutic index.

My understanding is that memantine did not end up working in clinical trials for treatment-resistant depression. Admittedly I haven't looked into the quality of evidence for Auvelity.

I've heard similar distaste from toxicology regarding bupropion. But is that at regular dosing or in overdose/interactions/impaired metabolism that they get concerned?

 

[Celexa]

My understanding is that memantine did not end up working in clinical trials for treatment-resistant depression. Admittedly I haven't looked into the quality of evidence for Auvelity.

I've heard similar distaste from toxicology regarding bupropion. But is that at regular dosing or in overdose/interactions/impaired metabolism that they get concerned?

It's that the dangers kick in very fast with very minor overdoses, as whopper talks about above. The therapeutic index is narrow and so even as little as someone accidentally taking 600mg for example, they have seen problems. They have the biases expected from a specialty who only deals with the times things go wrong and don't see all the success stories, but still, it's remarkable talking to them how bupropion sticks out among the commonly used antidepressants.

Compare to something like sertraline. Standard dosing for depression goes to 200mg and we might push up to 300mg or even 400mg for ocd. If someone accidentally takes a double dose of their high dose sertraline they might feel a little crummy but that's about it. People who take a double dose of wellbutrin 450mg have a meaningful risk of seizing even if otherwise healthy.

A quick search of the literature isn't very supportive for memantine but also is so limited it doesn't really seem conclusive in not being worth trying. With no pharma money incentive to do trials that's probably where the literature situation is going to stay....

 

[SmallBird]

Ketamine is also an NMDA antagonist, I suspect that as with SSRIs, the NMDA antagonists would still show some variation from one to another in their receptor affinities as well as efficacy

Actually wildly more so - immense variability in how different agents ultimately modulate glutamatergic tone.

 

[michaelrack]

xxx

 

[whopper]

But is that at regular dosing or in overdose/interactions/impaired metabolism that they get concerned?

A big problem, and this opens a Pandora's box with offering patients Auvelity or teaching them to mix Bupropion with DXM is there's no equation to converting how much is too much.
While the Bupropion in Auvelity is 105 mg per pill, and they can take up to 2 pills a day you can't simply say this is 210 mg/day. There's a competing metabolism effect with the DXM. So just how much does DXM 45 further elevate the 105 mg of Bupropion? I don't know, nor does anyone as of this writing. Bupropion in and of itself isn't as safe as an SSRI or SNRI, but the DXM mixed into it in Auvelity creates a new X-factor with danger that we are still in the newbie phase of understanding. This may open a new area of clinical research.

We do know that the Bupropion in Auvelity, only if taken in the recommended dosing is safe for most. Some of the reseaerchers may have encountered what are the upper limits of safety, but none of this data is published for us to peruse for ourselves.

Seriously, I'm thinking of writing a smartphrase with Auvelity that the patient better phukin not mess with the medication outside of my dosage recommendations. While it goes without saying even if it's not written in the notes, we've all had patients inappropriately play with meds.

I've never had the "act as if the med is radioactive" mentality unless it was an benzo, MAO, TCA, or lithium, but I've now adopted that with Auvelity after 1 patient who was fully stabilzed still ended up in the ICU. I remember when he got out of the ICU and thankfully fully recovered. The guy pretty much, on his own, was almost on his knees, almost crying for forgiveness for taking the med outside of recommended dosages. Had he not I was considering terminating him cause that was the only med that worked on his treatment-resistant/suicidal-level depression.

 

[calvnandhobbs68]

A big problem, and this opens a Pandora's box with offering patients Auvelity or teaching them to mix Bupropion with DXM is there's no equation to converting how much is too much.
While the Bupropion in Auvelity is 105 mg per pill, and they can take up to 2 pills a day you can't simply say this is 210 mg/day. There's a competing metabolism effect with the DXM. So just how much does DXM 45 further elevate the 105 mg of Bupropion? I don't know, nor does anyone as of this writing. Bupropion in and of itself isn't as safe as an SSRI or SNRI, but the DXM mixed into it in Auvelity creates a new X-factor with danger that we are still in the newbie phase of understanding. This may open a new area of clinical research.

Im going to say this as nicely as possible after my last post…it’s still not clear you actually understand the “why” of this combination.

It’s not the DXM that’s inhibiting the metabolism of bupropion. It’s bupropion that’s inhibiting the metabolism of DXM. DXM is technically the more “active” component of this combination.

The DXM “elevates” the 105mg of bupropion basically not at all, they do know, look at the FDA insert if you don’t believe me. They have to do the pharmacology data, the have the half lives, Cmax, etc all there.

There is no “competing metabolism effect” either, they aren’t metabolized by the same enzyme. You said this before when you were talking about giving bupropion with viibyrd and trintillex (viibryd isn’t even metabolized by cyp2d6 so I don’t even know what the viibryd thing was about).

This is like Symbyax vs giving fluoxetine and olanzapine alone. There’s nothing special about the bupropion dose. What I would be careful about is the dextromethorphan dose since that’s the thing whose metabolism is actually inhibited.

I’m bringing this up again because other people are going to read these posts and get confused.

 

[FlowRate]

Im going to say this as nicely as possible after my last post…it’s still not clear you actually understand the “why” of this combination.

It’s not the DXM that’s inhibiting the metabolism of bupropion. It’s bupropion that’s inhibiting the metabolism of DXM. DXM is technically the more “active” component of this combination.

The DXM “elevates” the 105mg of bupropion basically not at all, they do know, look at the FDA insert if you don’t believe me. They have to do the pharmacology data, the have the half lives, Cmax, etc all there.

There is no “competing metabolism effect” either, they aren’t metabolized by the same enzyme. You said this before when you were talking about giving bupropion with viibyrd and trintillex (viibryd isn’t even metabolized by cyp2d6 so I don’t even know what the viibryd thing was about).

This is like Symbyax vs giving fluoxetine and olanzapine alone. There’s nothing special about the bupropion dose. What I would be careful about is the dextromethorphan dose since that’s the thing whose metabolism is actually inhibited.

I’m bringing this up again because other people are going to read these posts and get confused.

What's really strange about Auvelity is that, if the NMDA antagonism is actually the useful mechanism, Auvelity should be worse than dextromethorphan alone, because you're inhibiting metabolism of dextromethorphan into dextrorphan, which has much more potency at NMDA receptors than DXM itself.

 

[mistafab]

Im going to say this as nicely as possible after my last post…it’s still not clear you actually understand the “why” of this combination.

It’s not the DXM that’s inhibiting the metabolism of bupropion. It’s bupropion that’s inhibiting the metabolism of DXM. DXM is technically the more “active” component of this combination.

The DXM “elevates” the 105mg of bupropion basically not at all, they do know, look at the FDA insert if you don’t believe me. They have to do the pharmacology data, the have the half lives, Cmax, etc all there.

There is no “competing metabolism effect” either, they aren’t metabolized by the same enzyme. You said this before when you were talking about giving bupropion with viibyrd and trintillex (viibryd isn’t even metabolized by cyp2d6 so I don’t even know what the viibryd thing was about).

This is like Symbyax vs giving fluoxetine and olanzapine alone. There’s nothing special about the bupropion dose. What I would be careful about is the dextromethorphan dose since that’s the thing whose metabolism is actually inhibited.

I’m bringing this up again because other people are going to read these posts and get confused.

I think he may have been referring to pharmacodynamic effects, not pharmacokinetic. Pharmacokinetically, it’s clear it’s the bupropion inhibiting metabolism of dex. However, pharmacodynamically, perhaps there is are unquantified effects on seizure threshold that happens in reverse or in combo.

 

[whopper]

Which is what I meant. For example in the patient I brought up this patient didn’t take much more than the 450 max dose of Bupropon (took about 550 mg in 1 day) and had a seizure that put him on the ICU.

Someone could argue he went over the FDA max but hardly so. Interactions between meds and enzymes can someone be highly conplex. Of course there’s some exceptions for slow and fast metabolizers, the patient wasn’t reliable from the beginning, and bupropion while having more seizure risk is usually a very safe med if directions are followed correctly.

 

[calvnandhobbs68]

I think he may have been referring to pharmacodynamic effects, not pharmacokinetic. Pharmacokinetically, it’s clear it’s the bupropion inhibiting metabolism of dex. However, pharmacodynamically, perhaps there is are unquantified effects on seizure threshold that happens in reverse or in combo.

That might theoretically make sense except there continues to be references to a “competing metabolism effect “ (there isn’t one) and “you can’t simply say this is 210mg a day” (you can).

We give Wellbutrin all the time with medications that could theoretically impact the seizure threshold, including SSRIs and SNRIs. I find it hard to believe dextromethorphan would impact this any more significantly. Sure, you could overdose on any of these medications but there’s not a solid reason to believe this is any scarier than me prescribing someone Wellbutrin XL 300mg a day.

 

[calvnandhobbs68]

What's really strange about Auvelity is that, if the NMDA antagonism is actually the useful mechanism, Auvelity should be worse than dextromethorphan alone, because you're inhibiting metabolism of dextromethorphan into dextrorphan, which has much more potency at NMDA receptors than DXM itself.

lol it’s like the esketamine vs ketamine thing…gotta do something so you can patent it.

Yeah I’m guessing their reasoning would be that you spread out the metabolism so long that you end up getting more coverage of the dextrorphan effect than you would otherwise. Most people get peak dextrorphan levels in just a few hours. Poor metabolizers (which is what you’re basically artificially doing with the 2D6 inhibition) also get 4x levels of dextromethorphan, so may outweigh the lack of initial conversion if you’re slowing down metabolism that much.

 

[mistafab]

That might theoretically make sense except there continues to be references to a “competing metabolism effect “ (there isn’t one) and “you can’t simply say this is 210mg a day” (you can).

We give Wellbutrin all the time with medications that could theoretically impact the seizure threshold, including SSRIs and SNRIs. I find it hard to believe dextromethorphan would impact this any more significantly. Sure, you could overdose on any of these medications but there’s not a solid reason to believe this is any scarier than me prescribing someone Wellbutrin XL 300mg a day.

I agree - yet if I had a patient have a seizure on what otherwise seems a benign combo (antidepressant and cough syrup), I may similarly be hesitant.

 

[clausewitz2]

I agree - yet if I had a patient have a seizure on what otherwise seems a benign combo (antidepressant and cough syrup), I may similarly be hesitant.

An antidepressant that is known to cause seizures in overdose and that the patient admitted overdosing on?

 

[FlowRate]

lol it’s like the esketamine vs ketamine thing…gotta do something so you can patent it.

Yeah I’m guessing their reasoning would be that you spread out the metabolism so long that you end up getting more coverage of the dextrorphan effect than you would otherwise. Most people get peak dextrorphan levels in just a few hours. Poor metabolizers (which is what you’re basically artificially doing with the 2D6 inhibition) also get 4x levels of dextromethorphan, so may outweigh the lack of initial conversion if you’re slowing down metabolism that much.

Dextromethorphan is renally cleared, so I doubt slowing conversion of it to dextrorphan increases the AUC of dextrorphan.

 

[clausewitz2]

Dextromethorphan is renally cleared, so I doubt slowing conversion of it to dextrorphan increases the AUC of dextrorphan.

There is always the possibility that inhibiting the conversion to dextorphan pushes metabolism towards usually non-dominant pathways, of which there appear to be many. I would be very interested in finding information on the dynamics of those usually minor metabolites.

 

[calvnandhobbs68]

Dextromethorphan is renally cleared, so I doubt slowing conversion of it to dextrorphan increases the AUC of dextrorphan.

It's been pretty well elucidated though that plasma concentrations stay pretty steady when you inhibit CYP2D6, which would likely increase the total amount of exposure because once it's converted dextrorphan is pretty rapidly glucuronidated and excreted. From my understanding its the final dextrorphan glucuronidation that is renally cleared.

Nuedexta is dextromethorphan/quinidine, so there's actually been quite a bit of research on what happens to plasma levels when you give it with a CYP2D6 inhibitor.

https://www.sciencedirect.com/science/article/pii/S0163725816300560?via%3Dihub

 

[Merovinge]

It's been pretty well elucidated though that plasma concentrations stay pretty steady when you inhibit CYP2D6, which would likely increase the total amount of exposure because once it's converted dextrorphan is pretty rapidly glucuronidated and excreted. From my understanding its the final dextrorphan glucuronidation that is renally cleared.

Nuedexta is dextromethorphan/quinidine, so there's actually been quite a bit of research on what happens to plasma levels when you give it with a CYP2D6 inhibitor.

https://www.sciencedirect.com/science/article/pii/S0163725816300560?via%3Dihub

Since you seem to know a lot about DXM, is there much data on Neudexta with mood? It would seem if the Wellbutrin is largely to CYP2D6 inhibit it should be similar to Auvelity? I feel so old now being out of training and not on the latest cutting edge with this psychopharm.

 

[calvnandhobbs68]

Since you seem to know a lot about DXM, is there much data on Neudexta with mood? It would seem if the Wellbutrin is largely to CYP2D6 inhibit it should be similar to Auvelity? I feel so old now being out of training and not on the latest cutting edge with this psychopharm.

ha I've just been looking more into Auvelity since ya know the drug reps are making their rounds...

But yeah I had the same question and it didn't look like there was a lot out there about Neudexta and depressive disorders. Theres some open label stuff but nothing that great. It looks like Otsuka did try to do a trial and I bet the results were negative since they never published it lol.

CTG Labs - NCBI

clinicaltrials.gov

 

[Stagg737]

There is always the possibility that inhibiting the conversion to dextorphan pushes metabolism towards usually non-dominant pathways, of which there appear to be many. I would be very interested in finding information on the dynamics of those usually minor metabolites.

There's not much good data out there on other metabolites from what I've seen (and I've looked into it). The main alternative pathway is conversion to 3-MM (which appears to have minimal clinical effect) by CYP3A4, but next step is also metabolized through 2D6 so you're inhibiting that pathway fairly early anyway.

What's really strange about Auvelity is that, if the NMDA antagonism is actually the useful mechanism, Auvelity should be worse than dextromethorphan alone, because you're inhibiting metabolism of dextromethorphan into dextrorphan, which has much more potency at NMDA receptors than DXM itself.

I think there's more to it than just NMDA antagonism. There's also been research on effects of antidepressants through AMPA receptor modulation by various substances that most I've interacted with believe are directly d/t NMDA effects, including ketamine and dextromethorphan. Idea is that actions on AMPA receptors directly modulates rapid rises in serum BDNF levels causing the rapid antidepressant effects. I wouldn't be surprised if that's playing a significant role with Auvelity as well as effects on NMDA receptors also lead to cellular changes in AMPAr activity.