How excited should we be about the latest class of antidepressants?
> As usual, insurances will cover it iff you can document you’ve tried lots of other stuff first, but I imagine
Lose something? :)
Time heals better than medicine though. After a few days, the improvement in placebo score was far more than any additional benefit generated by BRX60 or 90.
Some quick comments (might post more later):
Edit: the long version about progesterone became long enough to be its own blog post, which is now here: https://denovo.substack.com/p/progesterone-explained
1. There's no way it costs $10,000 to $20,000 a gram at scale. Those 3 chemical supply companies specialize in having a very large catalog of small quantities of chemicals for biologists to test in their experiments. (I have personally ordered from 2 out of those 3 for my research.) The price they charge per gram is not competitive at all.
Of course, if you want to buy 100g of allopregnanolone at $10,000/g, I'd be happy to make it for you.
2. For point 7 ( why not just give people progesterone?) In my opinion it seems like it should work, since it's the relevant precursor (and the fact that progesterone levels decline after birth is what's driving the decline of allopregnanolone). I'm interested in seeing your follow-up.
Created some prediction markets on Manifold Markets for your predictions here (with the starting prediction at your guesses and with the resolve date being March 8, 2027):
Zuranolone gets FDA approval for major depression: https://manifold.markets/Gabrielle/zuranolone-gets-fda-approval-for-ma
Zuranolone gets FDA approval for postpartum depression: https://manifold.markets/Gabrielle/zuranolone-gets-fda-approval-for-po
Zuranolone gets FDA approval for some other condition: https://manifold.markets/Gabrielle/zuranolone-gets-fda-approval-for-so
Another neurosteroid gets FDA approval for a psychiatric indication: https://manifold.markets/Gabrielle/another-neurosteroid-gets-fda-appro
Researchers become more convinced that allopregnanolone is an important regulator of brain anxiety states (at least as important as serotonin): https://manifold.markets/Gabrielle/researchers-become-more-convinced-t
The scientific consensus is still that allopregnanolone works by modulating GABA receptors in a way importantly different from benzodiazepines: https://manifold.markets/Gabrielle/the-scientific-consensus-is-still-t
Fellow chemists, help me with something weird about the chemicals I can't figure out: Allopregnanolone on Sigma costs 225$ for 10milligrams, but its acetate, which is essentially just adding a bit on the -OH group in the corner, costs nearly 500 times less! (270$ for 5 grams).
The chemical has only one hydroxyl group. No funky site-specific games are needed. Adding or removing the acetate on it should be extremely easy - acetic anhydride-alcohol condensation reactions (and the opposite - ester hydrolysis to alcohol and acid) are taught in 2nd year orgo labs. I find it hard to believe that running this reaction on 5 grams of the acetate costs 498 times more than the starting material.
I also don't think it's just purity - the acetate says 98%, but neither of them are listed as "pharmaceutical standard" (and those tend to be ~2-4x as expensive, not 500x). Purification costs money, but not *that* much.
Could it be a regulatory/tax issue? Or is there actual production chemistry I'm missing?
From Stahl's: 'the precipitous decline in circulating and presumably brain levels of allopregnanolone hypothetically trigger the onset of a major depressive episode in vulnerable women. Rapidly restoring neurosteroid levels over a 60-hour period rapidly reverses the depression, and the 60 hour period seems to provide the time necessary for postpartum patients to accommodate their lower levels'. So the idea is the taper of the steroid is a helpful part.
Also, (also Stahl's), there are two GABA-A receptors with comprosied of different sub-units as you mentioned. Benzodiazepines bind to, cleverly named, benzodiazepine-sensitive GABA-A receptors while allopregnalone bind to their cousins- the benzodiazepine-insensitive GABA-A receptor. The former is found post-synaptically and involved with phasic, quick bursts of GABA (i.e. useful information processing) while the latter is found extrasynaptically and involved with tonic (i.e. chronic) 'tone' setting of the neuron. So they seem to have very different functions despite both involving GABA.
Stahl's goes onto say that allopregnanlone 'hypothetically could cause more efficient information processing in over excited brain circuits causing symptoms of depression', but that just seems hand-wavy to me.
I have PMDD, klonapin made my depression worse. I've tried various BC's with little success. Anyone well versed in psychiatry want to study me ? I'd love to find a drug that works. (This is mostly facetious of course, but if someone is genuinely interested...)
Coincidence but I was researching zulresso and zushakon just yesterday.
Is PPD just depression after a specific event? Maybe?
I found some interesting results regarding the difference between plain major depressive episodes and PPD or PND. One study found that between women who were 0–12 months postpartum and women of childbearing age who were outside of the peripartum period rates of PPD and other depressive episodes did not differ in a statistically significant way (10.2% vs. 13.1%, respectively).
Additionally, people with a history of depression are significantly more likely to develop PPD. People who experience traumatic births (emergency C sections, long hard labors) are also more likely to develop PPD.
However, another study found that if women developed PPD in the first 8 weeks after birth the symptoms were more severe, more likely to be passed on, and had some epigenetic markers (not really sure what that means).
One issue is that PPD isn't well defined, some include developing symptoms up to 12 months after birth however others only include 6,8,12 weeks.
Entertaining, but not informative. Hard to say what medical science will say, if anything. They seem more interested in things that treat symptoms rather than diseases. Long term treatments seem to also be preferred by patients, too. Endless jabbering about their rare medical conditions seems to be the only activity that older people find enjoyable. Even Hugh Hefner seemed to enjoy talking about his (occasional, of course) flaccidity.
I wonder about the nutritional component or the use of oral pregnenalone. Rather to flood the body with additional supplies of hormonal building blocks rather than to attempt to up or down regulate various metabolic processes.
An extra 50mg a day of a 50 cent pill would be more viable for more people than some 4 day IV solution for 35k which almost no one would get until after their symptoms were already very bad. Even if pregnenalone capsules were not quite as good...perfect is the enemy of good.
It is a cheap and easy solution, hence probably one which would not get big pharma research dollars.
And in general a more nutrient oriented approach for post-partum issues when a woman's body is already going through an enormous torrent of metabolic changes seems like a wiser and more precautionary approach.
(I think it’s NMDA, not NDMA)
I wonder if it'd be helpful to have women at risk for PPD do a blood draw before giving birth and then get their own blood serum injected into them afterwards to even out the hormone shift....
I'm really curious about the progesterone->allopregnanolone thing. I find that I need to take the progesterone part of my feminizing HRT shortly before bed, because it tends to make me a bit drunk and sleepy. That's a known side-effect and I would love to know how and in what form it crosses into the brain to do that, given what you said in this post.
So apparently 13% of US adults are on some form of antidepressant, including 18% of women. This is up significantly in the last ten years.
I can't help but be reminded of the recent and equally American phenomenon of the over-prescription of painkillers, which everyone now seems to think was a Bad Idea. According to the popular narrative, some Big Bad Drug Companies managed to persuade everyone that any level of pain at all was unacceptable and should be treated with painkillers, damn the consequences.
Would it be reasonable to say that the Big Bad Drug Companies are doing similar things in the depression world, trying to pathologise ordinary levels of depression into something that requires drugs?
My thought is that we've already discovered a type of medication that works amazingly well for depression, anxiety, and nearly any other sort of suffering as well: the humble (yet loyal) opioid.
So we have a system in the brain that is directly linked to feeling good and suppressing pain. And we know opioids cause the most direct, intense and unalloyed mood lift available, and essentially erase depressive systems when administered (even and especially in treatment-resistant cases). And we know all kinds of other things in the brain can go a little bit wrong in subtle yet upsetting ways.
This suggests to me that probably a lot of cases of depression are due to some sort of malfunction with the individual's endogenous opioid peptides.
It also suggests to me that it's unsurprising when the search for something that will work just as well is littered with disappointments — anything that worked as immediately and dramatically as morphine would seemingly also have to be hitting some sort of "FEEL BETTER" button pretty hard, and the mOR is about the best one of those we've got.
Any miracle drug for depression would probably be found to just be an opioid in disguise, as indeed has happened more than once before (I predicted this, and was right about it, with kratom, tianeptine, and — possibly — also ketamine, though that one's still up in the air).
My father in India has cervical spondilosis. He wakes up from sleep with a head, back or shoulder ache. It gets better with massage, hot pad.
He was told it sounds like muscle tension maybe pinching on a nerve or a few ...
His cardiologist gave him Gabapentin 100 mg twice a day (sounds like what you talk about) for it. Sleepiness and feeling a bit off balance when walking have been 2 side effects of it. It made him so drowsy during the day that he decided to stop it. He tried a 100 mg once a day first.
It has been a week since he stopped that, and the side effects are not fully gone. Here, we don't get to see good doctors easily. There is a long wait.
I wonder if he should play with the dosage to fix the headaches and not have these effects. We found Lyrica to be similar (googlimg, not from a doctor) here at 75 mg, as Gabapentin is a capsule and 100 mg is the lowest. Is there a way to get advice on how to play with the dosage?
Pregnanolone (an isomer of allopregnanolone) is being studied to treat loneliness / perceived social isolation. I have tried it a few times... can't say I noticed much effect but I only tried it 2-3 times.
Given that loneliness is a rampant public health crisis, the fact that it has a fairly unique biological mechanism (neurons in the dorsal raphe nucleus), and the fact that loneliness is said to be worse for your health than smoking cigarettes, an effective medication for it would be amazing.
>>The “-pam” at the end stands for positive allosteric modulator!
I'm gonna go with urban legend for this one. The early benzos look to me to be chemically named; "azepine" is the word for a 7-membered ring made up of 6 carbon atoms and 1 nitrogen, then "diazepine" is the same but with two nitrogens. The first benzo was chlordiazepoxide (Librium), which if you look at the chemical structure on wikipedia, contains chlorine, diazepine and oxide (the oxygen atom). Then next is diazepam, which to me looks like "diazepine" plus "amide" (which is the word for "double-bonded oxygen atom with a nitrogen next door"). 10 years later we get alprazolam, which looks like it was named after the triazole ring (that's the 5-membered ring with 3 nitrogens), but now the "am" suffix is starting to become generic, to emphasise that its still in the same chemical class as the previous -azepams.
I doubt that the concept of "positive allosteric modulator" existed in 1955 when chlordiazepoxide was invented; in those days drugs were discovered by making random chemicals and feeding them to animals to see what happened. The receptor theory of medchem (i.e. that drugs have a specific biochemical target in the body) is generally credited to James Black and his fellow Nobel laureates, and propranolol (the first drug discovered in the target-based way) wasn't patented until 1962.
So the medication costs $35,000. Is it more effective than a $5 ketamine nasal spray? I kind of don't trust big pharma.
> psychopharmacology (motto: “Disappointing Doctors And Patients Since 1982”)
What's the significance of the 1982 date?
>>ROBIN, WATERFALL, MOUNTAIN, and CORAL
Now, hold on here.
ROBIN sacrifices herself to allow the Comet King to defeat Hell.
The Comet King fights Thamiel's army of demons using a WATERFALL from a broken dam.
A MOUNTAIN gets blown up when Sohu fights Thamiel and his forces.
Now where does CORAL come from here?
[epistemic status: kinda speculative]
Progesterone cream is already available OTC for $15. It absorbs transdermally into the bloodstream and thence is metabolized into the same thing as that $35,000 IV. A quick google search seems to indicate widespread off-label use of progesterone cream to treat PPD.
"pregnancy isn’t addictive" wait what? It definitely is for some. Just like opioids, actually.
I'm afraid that I'm a massive cynic of anti-depressants per se. Get into the cold sea, get out walking and stay largely away from coffee and alcohol and other stuff. Listen to Mozart, simplify your life, be with good people if you can, get fresh air, talk to strangers with kind faces, smile.
> It did give positive results, but the FDA reads the same biotech magazines I do and knows perfectly well what they did, so I don’t know what Sage expects to gain from this.
It wasn't clear if this is sarcasm that I'm missing, or if you really believe that the FDA cares about studies that game the system? I thought (maybe I'm misremembering) that you have in the past on this very substack lamented about how the FDA is at least mildly broken and it is well known how to game it by pharmaceutical companies?
Or perhaps I was over-reading between the lines to make your statements align with my own internal personal narratives. 🤷
Following on from what Himaldr said:
Opioids are very effective antidepressants; no one feels depressed while taking heroin for the first time. The problem is tolerance: Take the same dose of heroin every day and by day 7 it will have little to no effect, meaning you have to increase the dose to keep it effective. All drugs that increase happiness exhibit this phenomenon to a greater or lesser extent.
So the problem isn’t that we don’t have an effective treatment for depression. The problem is that effective depression treatments i.e. drugs that directly increase happiness, cause tolerance.
We therefore need to shift our pharmaceutical efforts away from producing endless variants of pharmaceuticals witch already exist (SSRIs, SNRIs, PAMs) and towards understanding and preventing tolerance.
We need to start developing and co-testing various anti-tolerance drugs with opioids to find a drug cocktail that prevents opioid tolerance. We can then administer this cocktail to anyone with depression, anxiety or any other kind of pain without risking addiction.
Like someone else mentioned, oral progesterone makes you feel very drunk and sleepy, likely because of conversion to allopregnanolone in the liver. I’m assuming the logic for not using oral progesterone is variance in liver enzymes which would lead to unstable and somewhat unpredictable amounts of allopregnanolone in the brain (waiting for the next post), in the same way SSRIs are prescribed instead of 5-HTP. However, from personal experience, it’s the best antidepressant and anti anxiety medication I have tried (and I have tried everything there is) and the results blew me away. My anxiety and depression vanished for the time I was taking oral progesterone, and it didn’t make me apathetic unlike SSRI/SNRIs, nor did it make me feel like I was drunk during the day like benzodiazepines. I am glad these molecules are being investigated for their antidepressant properties.
That might be a reach, but are you posting about postpartum depression as a roundabout way to celebrate international women's day?
Looking forward to the next post! I'm curious about the possible effects of progesterone on PMDD and I hope you'll discuss them.
If the mechanism of post-partum depression is a sudden decrease in GABA stimulation, how come it looks so different (clinically) from alcohol withdrawal or benzo withdrawal? People with alcohol withdrawal (or benzo withdrawal, which works via the same mechanism) have tremors, sweats, racing heart rates, and can have seizures if it's bad enough.
By the way, this isn't to say that I don't think allopregnalonone works! More so that GABA stimulation doesn't seem like it would be the mechanism?
What biotech magazines? I'm curious, and I want to read them!
the Demon-name is apt for a Sci who forces Swim Tests.
Pretty sure the suffix is "-azepam" and comes from "benzodiAZEPine AMide" since that describes the basic chemical structure.
> Maybe if you gave postpartum women an infusion of 300 mg Valium, and maximized your placebo effect by calling it the hot new thing, they’d do pretty well too (several days later, after recovering consciousness).
Comedy is bringing someone who ODd by taking a whole bottle of benzos to the ER and watching the physician swear. There's a reversal agent for benzos (flumazenil), but it has enough side-effects and risks that it isn't used unless it's really dire. So instead you need to find the patient an ICU bed for a couple of days to nap. You can't use a regular hospital bed because you need to account for the possible respiratory depression. But the ICU doesn't want to deal with this stuff, either.
Would it be possible to combine this in a depo- form for non-inpatient administration? Or would the sedating effects still be of concern?
re your #7, we've been giving progesterone for like 4 decades at the compounding pharmacy where I work, and we've been talking about its metabolism to allopregnanolone for about 20 years.
Notably, the route of administration MATTERS. A fraction of oral progesterone certainly seems to get metabolized to allopregnanolone and have -pam like effects, so a lot of HRT docs will write oral progesterone for bedtime administration as it seems to help with calming prior to sleep (it's -pam like, as you lay out, so it's not dissimilar from giving a z-drug for sleep pharmacologically).
topically administered and injected progesterone doesn't really seem to have comparable effects, likely due to bypassing the portal circulation and thereby the first-pass effect. At least that's how this works in my head. The standard of evidence in compounding land is a little lower than in big PhRMA manufacturing land.
Progesterone is also really cheap (at least in comparison to the insanity of brexanolone IV).
Hey Scott, just wanted to thank you for covering this topic. Hormones and their side effects can feel like a plague on the female body, especially since they are so poorly understood. The limited knowledge leaves women to rely on anecdote and trial by error to manage something that affects quality of life at nearly every waking moment (ok and sleeping moments too). Seems like the curiosity on this topic among researchers is not commensurate to percentage of humanity impacted. Looking forward to your post on progesterone.
Do we know that pregnancy is not addictive?
Evolution would tend to make it addictive. Plus, when you consider how inconvenient and dangerous it is, not to mention how much it f'n hurts to give birth, maybe addiction is playing some role?
Okay, I get it, I get it, evolution has dealt with this problem primarily by making sex addictive and . . . oh, hey, pregnancy, where did that come from? But still, do we really know? What's the evidence that you can't get hooked on pregnancy?
The names pharma comes up with for these new drugs are such grotesque, cynical neologisms. Yurolone, stabomab, perkopam. Fuck that shit.