I would say that the burden of superiority is higher for Auvelity than for most new antidepressants because of the BID dosing. Medication adherence, while more boring than neurobiology, probably make a bigger difference to reduction of depressive symptoms.
Also, the whole God thing was great. Your writing reminds me of the Experimental History Substack.
Glad you liked the God bit. Sometimes I read my stuff and think that it would be better delivered verbally (I mostly write how I would explain things out-loud), but glad it still lands with at least a couple of my readers!
My impression was that Auvelity got "fast-acting" bragging rights only because it was able to show statistically significant separation from placebo at week 1, which is something other SSRI/SNRIs generally fail to do. But otherwise, pretty similar outcomes, yeah.
In conversations I've had with folks who do use Auvelity, they say they've seen success with it in cases where SSRIs/SNRIs/Wellbutrin/Remeron have failed. I've seen a few patients who were already on Auvelity who said similar things about benefit, but I've also met with a few patients who tried Auvelity and didn't respond.
Thanks for commenting Awais. I think that the Posternak I mentioned in there suggests that -- at least when you look at them as a class -- the antidepressants really do separate from placebo by week 1.
As to it succeeding where others have failed, I mean, sure, I'm willing to believe in idiosyncratic cases, but I think I've heard that anecdote for almost every drug under the sun at this point!
Did Posternak and Zimmerman report statistical significance at week 1? [I don't have access to the paper, sorry]
In some of the other work I'm familiar with, e.g. Hieronymous et al, https://pmc.ncbi.nlm.nih.gov/articles/PMC4931602/ , they don't see statistical separation from placebo for SSRIs on HDRS total score by week 1, although there is a separation on depressed mood item.
Thanks for that Hieronymous paper, I didn't come across it while I was writing this up. It's certainly a statistically stronger paper than Posternak, so this does reduce my certainty in the conclusions I drew from its data.
Actually I just took another look at the Posternak data you included in the post and placebo is outperforming antidepressants at week 1, so clearly not statistically superior to placebo!
Hm, I think you're misreading it and I think I know how - probably my fault for not making this clear enough. The percentage that you're looking at is the percent of the total improvement at week 6 that occurred by the end of each week, but that doesn't say anything about the absolute amount of improvement.
To use a grossly exaggerated example: If total placebo improvement was 10 points at week 6, and all of that improvement happened in week 1, the percentage in that table would be 100%. If total antidepressant improvement was 100 points at week 6, but the improvement was only 15 points in week 1, the week 1 percentage would be 15%.
Is that a bit clearer?
The Posternak paper does not do a statistical analysis with p-values, but I'm not a diehard "I need to see p < 0.05 before I think it's true" kinda guy. I think the large N they have in that paper and the larger absolute improvement in the antidepressant group at week 1 suggests that there is true separation, but you're right that I can't represent that it's statistically significant separation.
To some extent, I do think it's a bit besides the point. Even if Auvelity is the only drug that statistically significantly separates from placebo at week 1, I don't think the clinical benefit is particularly impressive.
Ah, I get it now. Thank you for clarifying that! I do agree that the clinical advantage isn’t that impressive regardless of statistical significance.
With regard to anecdotal impressions, I recently met one psychiatrist who had a fair bit of experience using Auvelity with patients and ironically he thought that Auvelity worked well for his treatment resistance patients but in a *slow* acting manner, ie, he didn’t appreciate benefits until 2-3 months. Lol.
As you mentioned at the end, I'm not sure why this drug would be created if you can make a DIY version with bupropion SR 100 mg + DXM 45 mg BID, or something like that. It's hard to believe that the specific patented combination they made is so much more effective than a DIY combination (assuming that either is effective at all).
Auvelity is an "extended release" tablet, so the DIY is not going to recreate the exact pharmacokinetics. Nuedexta, notably, is only dosed once a day, which is a hint to me that the extended release might not really be necessary (though I literally just learned about that drug yesterday, so...) In any event, there are plenty of long-acting DXM formulations that are not that much more expensive than the instant-release stuff.
I had one patient who needed a renewal of prior auth on Auvelity, and for a period of two weeks, I ended up using the generic combo of bupropion SR and DXM, and patient said it went fine and he didn't notice a difference.
I definitely can't recall for sure but I thought I was taught 2-4 weeks for SSRIs instead of 4-6. That's definitely what I was telling people on new meds at retail though.
Loved the article! for some reason I just cannot get out of my brain the original ad they had for Auvelity, which is a woman in a blue jumpsuit with bubbles floating around. Like, why is she in a jumpsuit? Where did the bubbles come from? There has to be entire graduate programs around selecting what depressed people want out of remission, and apparently it involves jumpsuits (I would have settled for just sleeping normally).
Glad you liked it! It's actually a fun sort of game to figure out why this might be a good ad. My thoughts:
Women have 2x the rates of depression. This woman looks like late-20s/early-30s, so you cover the two age demographics that are most likely to suffer from depression and have kids. White women have higher rates of depression than other racial demographics, and are more likely to have higher end insurance/cash pay ability to afford a new drug. Artsy individuals (like mom obviously is here) also seem more susceptible to mood episodes (there's some literature on this, actually). Plus you're implying "Don't you want to be a good, happy mom? Definitely not a sad, depressed, bad mom."
High quality note. Thank you.
Great article, about a medication I’ve never come across in practice! Did it not impress you
that it was superior to another antidepressant, rather than just placebo as in most drug trials?
I wasn't impressed by the phase II trial because of:
1. Small N
2. The dose of bupropion used does not reflect real-world dosing, so I don't think you can really say it was "superior" to bupropion
3. Something obviously odd about the control group given how poor the bupropion efficacy was.
Not impressed overall because
1. It doesn't seem likely that it will be any better than any other antidepressant in terms of overall effect once we get more data
2. I don't think it's meaningfully faster in terms of onset
I would say that the burden of superiority is higher for Auvelity than for most new antidepressants because of the BID dosing. Medication adherence, while more boring than neurobiology, probably make a bigger difference to reduction of depressive symptoms.
Also, the whole God thing was great. Your writing reminds me of the Experimental History Substack.
A very solid point on the BID dosing, Paul.
Glad you liked the God bit. Sometimes I read my stuff and think that it would be better delivered verbally (I mostly write how I would explain things out-loud), but glad it still lands with at least a couple of my readers!
What do you think is the most promising Antidepressant in the pipeline in terms of efficacy?
Honestly, I don't really keep up with anything in the drug pipeline! I am still hopeful about psilocybin, but I'm not holding my breath.
My impression was that Auvelity got "fast-acting" bragging rights only because it was able to show statistically significant separation from placebo at week 1, which is something other SSRI/SNRIs generally fail to do. But otherwise, pretty similar outcomes, yeah.
In conversations I've had with folks who do use Auvelity, they say they've seen success with it in cases where SSRIs/SNRIs/Wellbutrin/Remeron have failed. I've seen a few patients who were already on Auvelity who said similar things about benefit, but I've also met with a few patients who tried Auvelity and didn't respond.
Thanks for commenting Awais. I think that the Posternak I mentioned in there suggests that -- at least when you look at them as a class -- the antidepressants really do separate from placebo by week 1.
As to it succeeding where others have failed, I mean, sure, I'm willing to believe in idiosyncratic cases, but I think I've heard that anecdote for almost every drug under the sun at this point!
Did Posternak and Zimmerman report statistical significance at week 1? [I don't have access to the paper, sorry]
In some of the other work I'm familiar with, e.g. Hieronymous et al, https://pmc.ncbi.nlm.nih.gov/articles/PMC4931602/ , they don't see statistical separation from placebo for SSRIs on HDRS total score by week 1, although there is a separation on depressed mood item.
Thanks for that Hieronymous paper, I didn't come across it while I was writing this up. It's certainly a statistically stronger paper than Posternak, so this does reduce my certainty in the conclusions I drew from its data.
Actually I just took another look at the Posternak data you included in the post and placebo is outperforming antidepressants at week 1, so clearly not statistically superior to placebo!
Hm, I think you're misreading it and I think I know how - probably my fault for not making this clear enough. The percentage that you're looking at is the percent of the total improvement at week 6 that occurred by the end of each week, but that doesn't say anything about the absolute amount of improvement.
To use a grossly exaggerated example: If total placebo improvement was 10 points at week 6, and all of that improvement happened in week 1, the percentage in that table would be 100%. If total antidepressant improvement was 100 points at week 6, but the improvement was only 15 points in week 1, the week 1 percentage would be 15%.
Is that a bit clearer?
The Posternak paper does not do a statistical analysis with p-values, but I'm not a diehard "I need to see p < 0.05 before I think it's true" kinda guy. I think the large N they have in that paper and the larger absolute improvement in the antidepressant group at week 1 suggests that there is true separation, but you're right that I can't represent that it's statistically significant separation.
To some extent, I do think it's a bit besides the point. Even if Auvelity is the only drug that statistically significantly separates from placebo at week 1, I don't think the clinical benefit is particularly impressive.
Ah, I get it now. Thank you for clarifying that! I do agree that the clinical advantage isn’t that impressive regardless of statistical significance.
With regard to anecdotal impressions, I recently met one psychiatrist who had a fair bit of experience using Auvelity with patients and ironically he thought that Auvelity worked well for his treatment resistance patients but in a *slow* acting manner, ie, he didn’t appreciate benefits until 2-3 months. Lol.
As you mentioned at the end, I'm not sure why this drug would be created if you can make a DIY version with bupropion SR 100 mg + DXM 45 mg BID, or something like that. It's hard to believe that the specific patented combination they made is so much more effective than a DIY combination (assuming that either is effective at all).
Auvelity is an "extended release" tablet, so the DIY is not going to recreate the exact pharmacokinetics. Nuedexta, notably, is only dosed once a day, which is a hint to me that the extended release might not really be necessary (though I literally just learned about that drug yesterday, so...) In any event, there are plenty of long-acting DXM formulations that are not that much more expensive than the instant-release stuff.
I had one patient who needed a renewal of prior auth on Auvelity, and for a period of two weeks, I ended up using the generic combo of bupropion SR and DXM, and patient said it went fine and he didn't notice a difference.
I definitely can't recall for sure but I thought I was taught 2-4 weeks for SSRIs instead of 4-6. That's definitely what I was telling people on new meds at retail though.
Loved the article! for some reason I just cannot get out of my brain the original ad they had for Auvelity, which is a woman in a blue jumpsuit with bubbles floating around. Like, why is she in a jumpsuit? Where did the bubbles come from? There has to be entire graduate programs around selecting what depressed people want out of remission, and apparently it involves jumpsuits (I would have settled for just sleeping normally).
https://cdn.bsky.app/img/feed_thumbnail/plain/did:plc:fbfgpenkvv6zxlte6aaz6y3b/bafkreibwtuxaxx7hg7pcuhaw6a6tzgtumyid7qxba4iskgoztajemkxtyu@jpeg .
Glad you liked it! It's actually a fun sort of game to figure out why this might be a good ad. My thoughts:
Women have 2x the rates of depression. This woman looks like late-20s/early-30s, so you cover the two age demographics that are most likely to suffer from depression and have kids. White women have higher rates of depression than other racial demographics, and are more likely to have higher end insurance/cash pay ability to afford a new drug. Artsy individuals (like mom obviously is here) also seem more susceptible to mood episodes (there's some literature on this, actually). Plus you're implying "Don't you want to be a good, happy mom? Definitely not a sad, depressed, bad mom."
Oh man, saw a low quality anime ad for Fanapt the other day.
Beautiful explanation of the molecular bio.
Pinging you on astrocytes https://substack.com/@jason780860/note/c-119782410