From what I can see, squinting at the table, there is a 2 point improvement on the depression scale at 1 week - are you really so sure that is clinically meaningful? I'd appreciate some guidance on accepted norms around the MDRS scale and clinical meaningfulness. I also note that it only increased to 5 point improvement by the end of the study - again, where does that sit? What point difference can you make on that scale with an improvement in somatic symptoms etc but no mood improvement?
I also note that it seems like most patients still were depressed at the end of the Auvelity study - and this is your yee-dee-dah celebration success?!!
Plus the buproprion only group which seems to be the comparison group had a response rate of only 15%, which is really low - I'm used to response rates for depression treatment more like 40%, so I'm wondering what's going on here??? Make the comparison group look really bad so that you look good in relief? It just raises questions... If the comparison group had the typical inert placebo response rate of 40%, the 45% response rate from Auvelity wouldn't look like much and it's certainly lower than the 60% response rate we were told was the standard ballpark response for ADs
These are genuine questions, I'm not just being a pain-in-the-arse medical student ;)
Erratum: response rates for ADs are more like 60% we've been taught, 40% placebo, (from a Oxford meta analysis I think (tho critics argue the differential response rates come from unblinding))
When I am not mid move i’ll have a more substantial response here …there are great points here; an I appreciate it. I just don’t have the time this week to give you a good answer and you deserve one given the strength of the questions!
Respectfully, Owen, I think your explanation for the potential mechanism of action here is very off the mark.
In the specific, I think you’re missing some key aspects of the role of the NDMA receptor in neuronal signaling. The NMDA receptor is an ion channel, but it does not drive action potentials in the short-term. Normally, there is a magnesium cation that sits right in the NMDAR’s channel and blocks calcium influx – the only way that the NMDA receptor opens is if the membrane it is in depolarizes. This knocks out that magnesium ion and allows the calcium to flow in. (It's also ligand gated and needs to be bound by glutamate *and* glycine, but that's not relevant here). The calcium, in this case, is not driving depolarization (that already happened) but is acting as a second-messenger (much in the way that the GCPRs do), and doing relatively “slow” things like Short Term and Long Term Potentiation.
In the general, this conceptual idea of ion channels as things that act “now” and GCPRs as things that make things happen “later” just doesn’t work. It’s very clear that LSD and the rest of the classic psychedelics do their thing by acting as agonists at 5-HT2A – a GCPR – and the onset of their (quite noticeable effects) is on the order of hours. Seconds, even, if we’re talking about DMT! The point is, second messenger mediated effects can happen quite rapidly.
I’m not saying that the NMDAR activity here isn’t important to the relatively quick onset of action; the fact that it shares this mechanism with ketamine is perhaps a hint. My point is that it’s pretty clear that the explanation can’t be explained by the fact that the NMDAR is an ion channel.
I’d also like to add that this idea that antidepressants really only kick in by week 6-8 is not supported by the literature, and a sizable fraction of the population (perhaps about 40% of responders) shows clinically meaningful improvement inside of 3 weeks (see: https://www.psychiatrist.com/jcp/early-delayed-onset-response-antidepressants-individual/) Not saying that there isn’t something to be said for a drug that could get everyone to respond within 2-3 weeks, but it's worth acknowledging that the 6-8 weeks thing is frequently overstated.
I wish had known this is 1997. I had a friend who was taking buproprion because ADD/ADHD had become fashionable, and the psychopharmacologist knew buproprion was slightly dopaminergic. She was convinced by the popular media that she had ADD/ADHD. Unfortunately, she got very sick, and I just wish I had known 😕 😔😔😔😔. .
From what I can see, squinting at the table, there is a 2 point improvement on the depression scale at 1 week - are you really so sure that is clinically meaningful? I'd appreciate some guidance on accepted norms around the MDRS scale and clinical meaningfulness. I also note that it only increased to 5 point improvement by the end of the study - again, where does that sit? What point difference can you make on that scale with an improvement in somatic symptoms etc but no mood improvement?
I also note that it seems like most patients still were depressed at the end of the Auvelity study - and this is your yee-dee-dah celebration success?!!
Plus the buproprion only group which seems to be the comparison group had a response rate of only 15%, which is really low - I'm used to response rates for depression treatment more like 40%, so I'm wondering what's going on here??? Make the comparison group look really bad so that you look good in relief? It just raises questions... If the comparison group had the typical inert placebo response rate of 40%, the 45% response rate from Auvelity wouldn't look like much and it's certainly lower than the 60% response rate we were told was the standard ballpark response for ADs
These are genuine questions, I'm not just being a pain-in-the-arse medical student ;)
There is a series coming out by @Nils Wendel, MD on this drug. He has pointed out my glib explanation is inaccurate and I believe him.
Might be best to wait for his take on these studies in the near future :)
T
Erratum: response rates for ADs are more like 60% we've been taught, 40% placebo, (from a Oxford meta analysis I think (tho critics argue the differential response rates come from unblinding))
When I am not mid move i’ll have a more substantial response here …there are great points here; an I appreciate it. I just don’t have the time this week to give you a good answer and you deserve one given the strength of the questions!
Cut my life into pieces…
For me, the era was much more "everything is keeping me together is falling apart/I've got this thing that I consider my only art..."
Respectfully, Owen, I think your explanation for the potential mechanism of action here is very off the mark.
In the specific, I think you’re missing some key aspects of the role of the NDMA receptor in neuronal signaling. The NMDA receptor is an ion channel, but it does not drive action potentials in the short-term. Normally, there is a magnesium cation that sits right in the NMDAR’s channel and blocks calcium influx – the only way that the NMDA receptor opens is if the membrane it is in depolarizes. This knocks out that magnesium ion and allows the calcium to flow in. (It's also ligand gated and needs to be bound by glutamate *and* glycine, but that's not relevant here). The calcium, in this case, is not driving depolarization (that already happened) but is acting as a second-messenger (much in the way that the GCPRs do), and doing relatively “slow” things like Short Term and Long Term Potentiation.
In the general, this conceptual idea of ion channels as things that act “now” and GCPRs as things that make things happen “later” just doesn’t work. It’s very clear that LSD and the rest of the classic psychedelics do their thing by acting as agonists at 5-HT2A – a GCPR – and the onset of their (quite noticeable effects) is on the order of hours. Seconds, even, if we’re talking about DMT! The point is, second messenger mediated effects can happen quite rapidly.
I’m not saying that the NMDAR activity here isn’t important to the relatively quick onset of action; the fact that it shares this mechanism with ketamine is perhaps a hint. My point is that it’s pretty clear that the explanation can’t be explained by the fact that the NMDAR is an ion channel.
I’d also like to add that this idea that antidepressants really only kick in by week 6-8 is not supported by the literature, and a sizable fraction of the population (perhaps about 40% of responders) shows clinically meaningful improvement inside of 3 weeks (see: https://www.psychiatrist.com/jcp/early-delayed-onset-response-antidepressants-individual/) Not saying that there isn’t something to be said for a drug that could get everyone to respond within 2-3 weeks, but it's worth acknowledging that the 6-8 weeks thing is frequently overstated.
I wish had known this is 1997. I had a friend who was taking buproprion because ADD/ADHD had become fashionable, and the psychopharmacologist knew buproprion was slightly dopaminergic. She was convinced by the popular media that she had ADD/ADHD. Unfortunately, she got very sick, and I just wish I had known 😕 😔😔😔😔. .