Hi! Psychiatrist here. Great writeup, I'm always happy to learn about breakthroughs in other specialties that I've lost touch with! It's especially nice to see long acting injectable medications develop outside of psychiatry.
I just wanted to make a couple comments about Xanomeline-Trospium to add nuance to the conversation.
In my view, the lack of side-effects is where the drug really shines - the antidopaminergics (i.e. previous antipsychotics) have a slew of movement and metabolic side effects that Xanomeline just doesn't. I expect it to become a first line treatment once it's off patent.
I think that the narrative regarding improvement of negative symptoms with xanomeline has been a bit misleading and frankly oversold. First, I don't think it's quite right to say that the antidopaminergics don't treat negative symptoms. They absolutely do, just not as well as the positive symptoms. Consider risperidone's effect size on positive symptoms (d = -0.61) vs. negative symptoms (d = -0.37). (Source: Huhn et al., The Lancet, Sept. 2019)
This isn't substantially different from the effect size on negative symptoms found in EMERGENT-2 (d = -0.40), and I don't think is substantially better than most antidopaminergics, which are somewhere around (d = -0.35). I'd also note that EMERGENT-3 did not show a significant improvement in negative scores at their endpoint.
My guess is that xanomeline-trospium will (unfortunately) look much like the other antipsychotics in terms of efficacy on negative symptoms as more data comes out, though I hope to be proven wrong!
I knew that a few previous antipsychotic also reduced negative symptoms, but had the impression that wasn't common. Based on what you've said, I'll look into it again and improve the phrasing.
On the EMERGENT trial, I noticed they did find an improvement in negative scores in their pooled results across all trials, which were very similarly designed. (See: https://www.nature.com/articles/s41537-024-00525-6#Fig2)
On metabolic side effects from previous antipsychotics, my understanding is that those were long-term and took some time to uncover, so I'm not sure if they're absent with xanomeline-trospium yet. Is that also your view? Thanks again!
I hadn't seen that pooled results paper! Good to know that the pooled data still show a strong signal for improvement in negative symptoms, though effect size is the same.
Re: Metabolic side-effects. Depends on what you mean by long term. Significant weight gain (>7% of baseline body weight) with the more metabolically deleterious antidopaminergics like olanzapine can be seen on the order of weeks. There's at least one paper that has shown changes in insulin resistance and lipid abnormalities in healthy controls after just a single dose!
The mechanisms of weight gain in the antidopaminergics are still being elucidated, but there are at least 2 major ones that I am aware of. (1) Dopamine does some paracrine signaling in the pancreatic islets to regulate insulin release; (2) H1 antagonism increases appetite. Clearly there is more going on here - risperidone does both of those things but only seems to feature weight gain, not dyslipidemia or insulin resistance.
However, xanomeline doesn't do either of those things. My hunch is that if there's no significant weight gain after 5 weeks (doesn't seem like there is in any of the EMERGENT data), that's a good sign that we won't see more. Still, we need to see what the long-term data says.
Omalizumab is also used to treat chronic urticaria (at least in France).
It has been a game changer for me. I used to have urticaria every day (itching and pimples everywhere) but since I've been injecting myself with Omalizumab once a month, I've had nothing.
"I find that frustrating — especially when there are genuine breakthroughs that have reached the final stages of testing that most people still never hear about ."
Inconsistent hyphenation:
"...health systems will need to find ways to make sure people who need them can actually get their twice-yearly shots" vs. "A six-monthly treatment injection" - should be consistent in using either "twice-yearly" or "six-monthly"
Unnecessary space after dash:
"For people with severe food allergies, exposure to small amounts of allergens can be life-threatening. Current treatments are typically taken after exposure to the allergen, although some people also try "oral immunotherapy" to train the immune system, where people have gradually increased doses of the allergen, but this takes months and can result in severe reactions if it doesn't work." (There's an extra space after the em dash in the original text)
Extra word "than":
"But for those taking osimertinib, this extended to 39 months — almost than three extra years." The word "than" should be removed.
Extra period in reference citation:
"Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial (2024)." has an extra period at the end while other citations don't.
Fascinating! While each breakthrough is remarkable, your concluding thoughts about the "regular stream of continuing progress" really resonated. The particular example of how clozapine's development "inspired much more innovation" in antipsychotic medication makes me wonder - do you see accelerating the overall process of medical innovation as potentially more impactful than any individual breakthrough?
I'm particularly struck by your point about how "incremental innovation" can make the difference between theoretical and practical effectiveness, like with the HIV prevention drugs. It makes me wonder about ways we could help speed up this innovation process. You mentioned potential "new pathways and incentives to accelerate research" - do you have thoughts on what these might look like? like are you personally involved in efforts to improve the innovation process, like through open science?
Would love to hear your perspective on what approaches you think are most promising for accelerating this "regular stream of progress" you described
With RFK in the news I like to remind people that most of his 2021 anti-Fauci book was actually about HIV drugs causing AIDS. So basically right before the medical establishment perfected HAART conspiracy theories developed that the meds were causing AIDS and HIV didn’t cause AIDS. And now it’s very clear that the meds effectively ended the AIDS epidemic and yet people like RFK are still pushing conspiracy theories from the 1990s!?!
Thought my comment from Bluesky would be helpful here, too: Hubs has been in treatment since June for Chronic Lymphocytic Leukemia. Amazed by his oncologist’s & care team’s enthusiasm. Any cancer dx is terrifying. But THANK SCIENCE! This seems to be a gratifying time to be doing such work. EVERYONE deserves this quality of care. And NOT going bankrupt to live.
Hi! Psychiatrist here. Great writeup, I'm always happy to learn about breakthroughs in other specialties that I've lost touch with! It's especially nice to see long acting injectable medications develop outside of psychiatry.
I just wanted to make a couple comments about Xanomeline-Trospium to add nuance to the conversation.
In my view, the lack of side-effects is where the drug really shines - the antidopaminergics (i.e. previous antipsychotics) have a slew of movement and metabolic side effects that Xanomeline just doesn't. I expect it to become a first line treatment once it's off patent.
I think that the narrative regarding improvement of negative symptoms with xanomeline has been a bit misleading and frankly oversold. First, I don't think it's quite right to say that the antidopaminergics don't treat negative symptoms. They absolutely do, just not as well as the positive symptoms. Consider risperidone's effect size on positive symptoms (d = -0.61) vs. negative symptoms (d = -0.37). (Source: Huhn et al., The Lancet, Sept. 2019)
This isn't substantially different from the effect size on negative symptoms found in EMERGENT-2 (d = -0.40), and I don't think is substantially better than most antidopaminergics, which are somewhere around (d = -0.35). I'd also note that EMERGENT-3 did not show a significant improvement in negative scores at their endpoint.
My guess is that xanomeline-trospium will (unfortunately) look much like the other antipsychotics in terms of efficacy on negative symptoms as more data comes out, though I hope to be proven wrong!
Thank you, and for the detailed comment!
I knew that a few previous antipsychotic also reduced negative symptoms, but had the impression that wasn't common. Based on what you've said, I'll look into it again and improve the phrasing.
On the EMERGENT trial, I noticed they did find an improvement in negative scores in their pooled results across all trials, which were very similarly designed. (See: https://www.nature.com/articles/s41537-024-00525-6#Fig2)
On metabolic side effects from previous antipsychotics, my understanding is that those were long-term and took some time to uncover, so I'm not sure if they're absent with xanomeline-trospium yet. Is that also your view? Thanks again!
I'd check out the Huhn et al. review from the Sept 2019 edition of The Lancet (https://linkinghub.elsevier.com/retrieve/pii/S0140673619311353) to see a good overview of the effect sizes of individual antipsychotics.
I hadn't seen that pooled results paper! Good to know that the pooled data still show a strong signal for improvement in negative symptoms, though effect size is the same.
Re: Metabolic side-effects. Depends on what you mean by long term. Significant weight gain (>7% of baseline body weight) with the more metabolically deleterious antidopaminergics like olanzapine can be seen on the order of weeks. There's at least one paper that has shown changes in insulin resistance and lipid abnormalities in healthy controls after just a single dose!
The mechanisms of weight gain in the antidopaminergics are still being elucidated, but there are at least 2 major ones that I am aware of. (1) Dopamine does some paracrine signaling in the pancreatic islets to regulate insulin release; (2) H1 antagonism increases appetite. Clearly there is more going on here - risperidone does both of those things but only seems to feature weight gain, not dyslipidemia or insulin resistance.
However, xanomeline doesn't do either of those things. My hunch is that if there's no significant weight gain after 5 weeks (doesn't seem like there is in any of the EMERGENT data), that's a good sign that we won't see more. Still, we need to see what the long-term data says.
Thanks very much! I've now updated that section and given you a little shout out. I really appreciate it.
Happy to help, discussions like these are what our work is all about, no? Keep up the good work!
Omalizumab is also used to treat chronic urticaria (at least in France).
It has been a game changer for me. I used to have urticaria every day (itching and pimples everywhere) but since I've been injecting myself with Omalizumab once a month, I've had nothing.
Typos:
Extra space before a period:
"I find that frustrating — especially when there are genuine breakthroughs that have reached the final stages of testing that most people still never hear about ."
Inconsistent hyphenation:
"...health systems will need to find ways to make sure people who need them can actually get their twice-yearly shots" vs. "A six-monthly treatment injection" - should be consistent in using either "twice-yearly" or "six-monthly"
Unnecessary space after dash:
"For people with severe food allergies, exposure to small amounts of allergens can be life-threatening. Current treatments are typically taken after exposure to the allergen, although some people also try "oral immunotherapy" to train the immune system, where people have gradually increased doses of the allergen, but this takes months and can result in severe reactions if it doesn't work." (There's an extra space after the em dash in the original text)
Extra word "than":
"But for those taking osimertinib, this extended to 39 months — almost than three extra years." The word "than" should be removed.
Extra period in reference citation:
"Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial (2024)." has an extra period at the end while other citations don't.
Thanks! I've corrected the 'six-monthly' inconsistency and removed the word 'than' there.
But strangely I don't see an extra space in those places or the extra period, on my end.
weird, maybe it got shifted when i copy and pasted
I was at AIDS2024 when they presented data for Lenacapavir ❤️
Fascinating! While each breakthrough is remarkable, your concluding thoughts about the "regular stream of continuing progress" really resonated. The particular example of how clozapine's development "inspired much more innovation" in antipsychotic medication makes me wonder - do you see accelerating the overall process of medical innovation as potentially more impactful than any individual breakthrough?
I'm particularly struck by your point about how "incremental innovation" can make the difference between theoretical and practical effectiveness, like with the HIV prevention drugs. It makes me wonder about ways we could help speed up this innovation process. You mentioned potential "new pathways and incentives to accelerate research" - do you have thoughts on what these might look like? like are you personally involved in efforts to improve the innovation process, like through open science?
Would love to hear your perspective on what approaches you think are most promising for accelerating this "regular stream of progress" you described
Thank you!
I've written a few articles about the topic:
- On the history of malaria vaccine development and how it could've been sped up: https://worksinprogress.co/issue/why-we-didnt-get-a-malaria-vaccine-sooner/
- Ideas to speed up science, using examples from the pandemic: https://www.wired.com/story/covid-19-open-science-public-health-data/
- How specialization and more division of labour in science could speed up the process: https://worksinprogress.co/issue/the-speed-of-science/
With RFK in the news I like to remind people that most of his 2021 anti-Fauci book was actually about HIV drugs causing AIDS. So basically right before the medical establishment perfected HAART conspiracy theories developed that the meds were causing AIDS and HIV didn’t cause AIDS. And now it’s very clear that the meds effectively ended the AIDS epidemic and yet people like RFK are still pushing conspiracy theories from the 1990s!?!
Thought my comment from Bluesky would be helpful here, too: Hubs has been in treatment since June for Chronic Lymphocytic Leukemia. Amazed by his oncologist’s & care team’s enthusiasm. Any cancer dx is terrifying. But THANK SCIENCE! This seems to be a gratifying time to be doing such work. EVERYONE deserves this quality of care. And NOT going bankrupt to live.
The world continues to get better just at a slow enough rate it isn't always obviouse.
Still no herpes cure…not that I have herpes I’m just sorry for those people. 😉
What biochemical or anatomical test confirms a diagnosis of “schizophrenia”’