Astral Codex Ten

GABA-A Receptor

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GABA-A Receptor

Article

GABA-A Receptor is a recurring concept in the Astral Codex Ten archive, appearing 2 times across 2 issues between March 08, 2022 and March 16, 2022. The archive places it in contexts such as “Biphasic Actions At The GABA-A Receptor here for an explanation”; “there are two GABA-A receptors with comprosied of different sub-units”; “tolerance to allopregnanolone with focus on the GABA-A receptor”. It most often appears alongside allopregnanolone, GABA, progesterone.

Metadata

  • Category: Concepts
  • Mention count: 2
  • Issue count: 2
  • First seen: March 08, 2022
  • Last seen: March 16, 2022

Appears In

Source Context

Recovered passages from the original issue text. When the raw archive preserved outbound links inside the source passage, they are listed directly under the quote.

Zounds! It's Zulresso and Zuranolone!
March 08, 2022 · Original source
Notice that lower doses worked better than higher doses. This is sometimes a red flag on a study. But this time it seems legit; see “Biphasic Actions At The GABA-A Receptor” here for an explanation. Both studies also evaluated side effects. These were generally mild, but two people (about 2% of the study population) lost consciousness. Nothing seemed wrong with them, and researchers mostly attributed this to allopregnanolone being a sedating drug. If you sedate people too hard, they pass out. Faced with these results, the FDA approved allopregnanolone for post-partum depression, but subjected it to a REMS (Risk Evaluation And Mitigation Strategy) - basically, doctors who want to prescribe it will need to take special courses and do extra paperwork. This kind of surprised me - there are plenty of sedating drugs that make you pass out in overdose. Also, since patients will be getting it IV, there will probably be a nurse around to check if they passed out and take appropriate actions if so. But the FDA really likes putting restrictions on things, and I guess this was a free chance for them to do that. 4: Is Zulresso freely available at a doctor’s office near me? It’s possible to get Zulresso, but really hard. Because Zulresso is an IV infusion lasting four days, you need to spend four days somewhere that people can put an IV into you and monitor it. Realistically that means a hospital or some other big medical institution. So this is only available for inpatients. Because of the REMS (extra certification and paperwork), most hospitals aren’t interested. You can find a list of ones that are here - it looks like there are about 89 locations in the US with the right certification. Last but not least, a four-day course of Zulresso costs $35,000 for the medication itself, plus much more for the four-day hospitalization it takes to receive it. As usual, insurances will cover it iff you can document you’ve tried lots of other stuff first. 5: Hold on, does it really cost $35,000? Oho, I see you’ve played the “pharma price analysis” game before. But this time I think the price might actually be defensible. Chemical supply companies (1, 2, 3) generally sell allopregnanolone for $10,000 to $20,000 a gram. (I found one company with a much lower price, but I’m suspicious and am going to dismiss them as an outlier). The usual dose of allopregnanolone is 60 ug/kg/hour x 60 hours, which for a 60 kg person comes out to a total of 0.25g total. Getting that amount from the chemistry supply store would cost about $2,500 - 5,000. I assume pharma-grade allopregnanolone is more expensive than chemistry-store-grade, so it wouldn’t surprise me if a price in the low five-figures was justified by manufacturing alone. Isn’t it still a pretty good deal to find an endogenous neurosteroid, do one or two studies confirming it’s great, produce it for the low five figures, then sell it for the mid five figures? I think maybe not. This drug has a terrible value proposition. Post-partum depression is one of the rarer psych conditions. Most people with PPD won’t check into a hospital and pay $35,000 for a drug infusion. And the people who do will get the drug infusion, feel better, and never need it again (at least until they have another kid) - unlike SSRIs where you can keep charging for monthly prescriptions forever. Sage Therapeutics, the pharma company that owns the patent on Zulresso (and nothing else - this is their only drug!) has done terribly. Their stock is in the doldrums, they almost went bankrupt, and they survived only with the help of a cash infusion by a bigger pharma company. I think this confirms a general trend where at least some expensive medications are pricey because of fundamentals (including regulatory fundamentals) and not just pharma companies making obscene profits. 6: Hold on, how is allopregnanolone different from benzodiazepines? Remember, allopregnanolone is a positive allosteric modulator of GABA, much like benzodiazepines such as Xanax. But Xanax is cheap ($10 for 30 pills). And you can get it at any local pharmacy (plus sometimes on street corners). What’s so special about allopregnanolone that you should pay $35,000 and go into the hospital to get it? The official answer is “allopregnanolone modulates GABA differently from benzodiazepines”. For example, this paper says that: Allopregnanolone allosteric modulation of the action of GABA at GABA-A receptors is much less selective than that of benzodiazepines, which are relatively inactive at α4- or α6-containing GABA-A receptors. If you really like details about receptor subunits, this paper presents the full case. The skeptic’s answer is “who knows?” Psych drugs often work for reasons totally different than we thought. People thought tianeptine was an SSRE for years, until it turned out to be a mild opioid. People thought ketamine was NMDA-ergic for years, until it turned out to be [fill this part in 10 years from now]. Last year a bunch of very smart people tried to claim that SSRI effects had nothing to do with serotonin (I think they were wrong). Just because some guy found that Zulresso acts as a GABA-PAM in some test tube doesn’t mean that’s what’s having any of the relevant antidepressant effects. The troll’s answer is “who says it’s different?” Do benzodiazepines treat depression? Depends who you ask. If you ask benzodiazepine users, their answer is “yes, definitely”. If you ask drug warriors, their answer is “Addictive Substances May Make You Temporarily Feel Good, But They Are Not A Responsible Treatment Option”. If you ask the research literature, it gives vague indeterminate answers, as always. But nobody has ever said benzodiazepines instantly and miraculously cure depression, so how come allopregnanolone seems to do that? A true troll would point out that we probably give allopregnanolone at much higher doses - 2% of allopregnanolone patients were sedated so hard they lost consciousness, whereas this is exactly the sort of side effect I try to avoid when calculating benzodiazepine doses. 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). I think the troll answer would be hilarious but I don’t really want to defend it as correct; if I had to bet I’d say the official explanation is the right one. 7: Hold on, why can’t we just give people progesterone and let them metabolize it into allopregnanolone? This turned out to be an interesting enough rabbit hole that I’m going to spin it off into another post later this week. 8: Hold on, people have lots of allopregnanolone when they’re pregnant, right? And then post-partum depression happens when they give birth, and their allopregnanolone level drops. So if you give someone an infusion of allopregnanolone, and then take them off it, that’s a hormonal simulation of giving birth, ie the same thing that caused the problem in the first place? How is that good? Oh, you think you’re clever, do you? What you failed to consider is . . . I didn’t end that sentence because I can’t find anything in the literature addressing this question. But the difference might be that the infusion schedule ramps up gradually, peaks, and then ramps down gradually, which is more of a soft taper than the sudden crash of birth. If anyone knows more about this, please let me know. [EDIT: see this comment] 9: Is allopregnanolone addictive? No, because good luck getting addicted to a $35,000-per-dose chemical. We should probably expect allopregnanolone to be addictive, by analogy to other GABA-PAMs like benzodiazepines and alcohol. But nobody has ever received more than a single dose. You don’t get addicted to benzos after a single pill, or alcohol after a single beer, so in practice AFAIK nobody has ever gotten addicted to this. Or who knows, maybe it’s not addictive. Remember, allopregnanolone is naturally elevated during pregnancy; pregnancy isn’t addictive. And some scientists claim the brain endogenously uses allopregnanolone as a master regulator of depression and anxiety. In theory, if you could give yourself the same amount a non-anxious person’s brain gives them all the time, shouldn’t you be no worse off than that non-anxious person? I don’t know, and remember that your brain also has a lot of endogenous opioids; doesn’t make the exogenous kind any safer. The Drug Enforcement Administration has made Zulresso a Schedule IV controlled substance, which means they’re putting a few very weak restrictions on it but not worrying too much. 10: Does allopregnanolone work for depression that isn’t post-partum? If all psychiatric disorders are secretly allopregnanolone imbalances, then you might expect it to work on all depressions, not just post-partum. I’m sure pharmaceutical executives with dollar signs instead of pupils in their eyes have had this same thought, but I can’t find studies about it. Some of the same people behind the postpartum studies did a very small, very weak study on ganaloxone (a close allopregnanolone relative) for persistent depression; it seemed to work, but also caused a lot of sedation (more than in the postpartum trials? Hard to tell). Nobody’s looked into this further since then, maybe because that was around when the pharma companies realized that the 4-day hospital stay and $35,000 price tag made allopregnanolone a financial loser. The evidence from zuranolone (see below) suggests that allopregnanolone might not work very well against regular depression. 11: What is zuranolone? Wikipedia describes zuranolone as “a swirling, black vortex revered by the Mutsune Native Americans as a dire death god . . . also worshiped by mysterious servitors known as the Hidden Ones.” No! Sorry again! That’s Zushakon, another Great Old One. Zuranolone is Sage Therapeutics’ attempt to turn allopregnanolone into an accessible medication that might actually make them real money. Zuranolone is mostly just allopregnanolone with some extra stuff attached that changes the absorption. Zuranolone can be taken orally, so you don’t have to go to a hospital for four days to receive it IV. It’s potentially less likely to cause loss of consciousness and other undesirable side effects. And it’s under investigation as a potential treatment for postpartum depression, bipolar depression, regular depression, insomnia, and various movement disorders. (that might seem excessive, but benzodiazepines treat a lot of stuff, and if these neurosteroids are kind of like super-benzodiazepines, then this level of optimism might be warranted.) 12: Does zuranolone work? Sage Therapeutics answered this question the same way pharma companies answer every question: with a bunch of studies whose names form overly-cute acronyms. We’ll talk here about ROBIN, WATERFALL, MOUNTAIN, and CORAL - though I assure you there are others. ROBIN tested efficacy in postpartum depression. Results were positive and relatively impressive, about the same as the weaker allopregnanolone studies. WATERFALL, MOUNTAIN, and CORAL tested results in regular depression. WATERFALL was positive but weak. MOUNTAIN was negative. That scared the pharma company and they hacked CORAL to be more likely to give positive results. 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. Overall these trials were disappointing. I think the most likely story is that allopregnanolone = zuranolone, both are moderately effective in postpartum depression, and both have much less efficacy in regular depression, probably not literally zero but also not enough to be worthwhile antidepressants (especially considering cost). Might zuranolone be an excellent anti-anxiety medication? You’d think so - it should be at least as good as benzodiazepines, which are excellent anti-anxiety medications. And researchers seem excited about allopregnanolone as a master regulator of brain anxiety. But the studies aren’t promising. ROBIN and WATERFALL incidentally assessed anxiety; ROBIN found good results in its postpartum population, but WATERFALL found poor-to-mediocre results in its regular population. Studies are hard, and sometimes even really effective drugs can have trouble showing strong results. But these aren’t encouraging. 13: So where do we go from here? Getting FDA approval for zuranolone for postpartum depression seems reasonable; it’ll probably be cheaper and easier than making people go to the hospital to get allopregnanolone. I’m uncertain about the financials of this for Sage, but since they did the study they hopefully think it’s worth it. Otherwise, I’m not sure. It would have been great if zuranolone had shown robust efficacy against regular depression and anxiety, but this is exactly the kind of great thing that never happens in psychopharmacology (motto: “Disappointing Doctors And Patients Since 1982”). It might be worth throwing it against anxiety disorders and PTSD to see if anything sticks, but I wouldn’t bet on it. The research into allopregnanolone as master regulator of brain anxiety states is fascinating, but as far as I know it hasn’t reckoned with the failure of zuranolone to really treat much anxiety. The cynical part of me predicts that once pharma’s done making money off neurosteroids then all of this will die down, and something else that pharma can make more money from will become the master regulator of everything. I expect that the main thing we get out of all this is somewhat better post-partum depression treatment, which might or might not ever become accessible for ordinary people. 14: Predictions In the next five years… Zuranolone gets FDA approval for major depression: 15%
Inline links: here, here, 1, 2, one company, has done terribly, this paper, this paper, tried to claim, their answer is, their answer is, it gives vague indeterminate answers, this comment, a very small, very weak study, describes, https://substackcdn.com/image/fetch/$s_!hqfF!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F5b386f78-93b3-4d16-98c4-6d2eedef5a1f_548x256.png, ROBIN, WATERFALL, MOUNTAIN, CORAL, to be more likely to give positive results
Highlights From The Comments On Zulresso
March 16, 2022 · Original source
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.
Key point missing in this post is that ALLO/zulresso mediates tonic GABA inhibitory tone (as opposed to phasic for benzos). I wouldn't touch an exogenous analog of ALLO w/ a ten foot pole. Context on severe issues w/ tolerance and withdrawal: Tolerance to allopregnanolone with focus on the GABA-A receptor.
Inline links: Tolerance to allopregnanolone with focus on the GABA-A receptor
The claim that progesterone doesn't have any side effects at the doses you're talking about is very contrary to a lot of testimonials as well as pharmacological effects that should be kind of obvious. The metabolite you're trying to maximize here is a a GABA-A receptor agonist, which is going to give it somewhat intoxicating, sedative effects heading towards nauseating and disorienting as dosage trends upwards. It can also significantly spike your libido. These aren't totally bad effects and they might even be a part of what you want for treating PPD, but saying "there's no side effects" is just not true.