Ooh, I love the new predictions at the bottom in the nifty boxes! Also, I just want to say how much I appreciate you being back. I get genuinely happy every time I see there's something new to read, because I know it's something worth reading and is absolutely thought-provoking. Thanks so much, Scott!
I'm already regretting my predictions on this one - after thinking about it more, I ought to be at least 97% sure of the second one - but I don't have good norms in place for deciding when I can edit predictions, so I'll just mention it here.
Considering the... lugubrious nature of the FDA (Not a bad thing!), and the long pipeline that drugs have to take, I would put it around 99.9% for me. Only mitigating factor I can think of is that SSRIs have been around long enough that I'm sure pharma companies are licking their chops at being able to pioneer a brand new method of action in marketing to doctors. And this is all assuming the effect is real!
Second note: Love the wit on the caption on the picture. I have no idea how you write it, or how you wrote Unsong. You're a wizard.
On the topic of editing predictions: I would find it *most* compelling if predictions were mutable until some change in material conditions or in availability of information occurred. In particular, why not let comments influence them for a few days (perhaps with notes of adjustments)?
Authorial opinion modulated by community opinion a la Tedlow would produce the most interesting bets, imo.
imo it's entirely reasonable to update predictions w some kind of timestamped changelog. Just add the revision below with your new reasoning (& probably only use it for ~relatively timely updates, e.g. w/i a day or week of posting)
Maybe you should consider writing predictions as ratios instead of as percentages. It makes it eaasier to make more exteme predictions when necessary, e.g. 1:30 vs 1:20.
I wonder if duration of discontinuation syndrome sheds any light on the long buildup claim. Looks like the standard answer is that brain zaps last a few weeks tops, but I seem to recall them lasting months, and I see other reports of that when I dig beneath the surface. Seems like something that could easily be underestimated.
> Also, all these mice studies are great, but in human studies, SSRIs barely work. The best meta-analyses of thousands of depressed patients manage to pick up a small signal, assuming the pharma companies haven’t figured out some way to fake us all out.
This is the part that bugs me the most. How can you claim to have discovered the mechanism behind an effect that, as far as I can tell, may not even exist?
It's well know that compounds with basic amines (e.g. amantadine, monamines, etc) accumulate in lysosomes. The basic mechanism is simple: uncharged molecules generally pass through cell membranes more easily than charged molecules. At physiological pH a small fraction of basic amines (~0.1%) will be uncharged. In lysosomes however, which are 2-3 pH units lower, only 0.001-0.0001% will be uncharged.
In a slightly simplified scenario where only uncharged compounds can pass through membranes, there will be roughly 100-1000x more compounds capable of entering a lysosome than of exiting one at any given moment. This essentially means lysosomes are sinks for basic compounds.
I'm not sure how this would affect overall brain accumulation, especially over week-long periods, but it does make the AD accumulation bit seem a bit more plausible.
Scott, how open are you to giving scientific talks about these issues in a university setting? (Either in person or more likely Zoom). I organize the lab meetings for my neuroscience lab at Hebrew University (Jerusalem) and we'd be happy to get your perspective. (I've recently been working on models/ideas that involve BDNF and plasticity so this is especially interesting to me).
I don't actually know anything about this, I'm making it up as I go along with a lot of help from Google Scholar. Also in general I don't give talks, sorry.
There are quite a few sentences that end with question marks without much good reason in this piece? It's the first time I've noticed that in Scott's writing?
see https://slatestarcodex.com/2016/02/20/writing-advice/. It's a useful way share uncertainty/confusion with the reader. "Defend your flow of ideas at all costs. This might sound paradoxical after section 2, which was about how breaking flows is great. It is kind of paradoxical, and it is sort of hard to explain, but it’s the difference between 'exciting' and 'horrible'."
Yeah, I think instead of the technically grammatically prescribed "question marks are used to mark questions", he's using question marks to mark the upward inflection of spoken speech that we use when we're unsure about what we're talking about, even when the statement isn't grammatically a question.
The "something something" remarks read (to me anyway) like he is cynical about findings from certain molecular biology experiments. Many of which are routine in academic and commercial labs where this kind of research is conducted. They represent the kind of hard, painstaking scientific work that must be done (and has been done) to understand molecular function in order to develop effective drugs. To then say - "I'm not a cellular biologist or a biochemist, so I can't comment on most of the high-tech methods used in this paper." - begs a different question: So why did you?
OTOH, I found it a minor refreshment from the usual "genes something something genes."
How *do* you figure out whether a mouse is depressed? (if our animal models were cetacean rather than rodentine, would our inventories find porpoises more depressed than dolphins?)
The system is inherently abusive. I wonder how Björkholm et al correct for the baseline fear & anxiety of animals being caged, stabbed with needles, and [ultimately] decapitated or mass-gassed? [or stabbed yet again, intracardially.]
"Cortisone levels rise in monkeys watching other monkeys being restrained for blood collection. Blood pressure and heart rates elevate in rats watching other rats being decapitated." [Aysha Akhtar, The Flaws and Human Harms of Animal Experimentation. Cambridge Quarterly of Healthcare Ethics, 24[4] [2015], 407–419.]
I wonder if we're ready to talk about the moral contradiction of brutalizing our psychological kin. I mean: these studies are relevant to human Psychology only because the beings being abused in them are like us in morally relevant respects. I.e. maternal deprivation experiments on rats work because rat mothers and pups love each other. Or something analogous enough to your "love" to be data-relevant.
On the other hand, these studies risk being irrelevant because they can't correct for all the inherent abuses. I.e. Almost all animal studies are maternal deprivation studies, unacknowledged.
To be fair, at least within the EU the well-being of lab animals in public institutions at least has massively improved and you actually need to explain the ethics of your experiment, the ways you'll minimize harm to the animals etc. before they let you stab them. I spoke to some people involved with our local medical university's animal research and they seemed way more ethical than the average meat eater, tbh.
What's going on behind closed doors of corporate R&D is, I imagine, not as pleasant.
I have hope in the rise of non-animal models, where the EU seems to be ahead of N.America, predictably. Non-animal models [The Johns Hopkins Center for Alternatives to Animal Testing is a trove of info on this & related] may take over Toxicology in the coming decades, but it's hard to see how Psychopathology could do the same.
Nice people, yes. Animal Care Ethics Committees, yes. The banality of Civilization's evil - it's mainly "decent" people, conscientious in their way, who do the City's monstrous work.
Hard to say things have improved for animals when our manipulations of them have only deepened since the days of Pavlov. Their steel cages might be a tad bigger, but we genetically cage & cripple them now. Our repertoire of sadism only expands, yet the sadism is hard to spot at the personal level - I too have spoken with many intelligent & sensitive animal researchers.
And hard to separate College from Corporate lab, when the former are used to publicly fund proprietary gains for that latter, and the profs consult happily for Pfizer et al.
I can only speak from my own experience at my institution (Georgetown University) and with the model organism I have used (mouse). As far as I am aware, much of this is similar for rats.
Mouse cages are plastic, not steel, and aside from bedding, food and water ad lib., they typically feature an enrichment toy (e.g. a plastic cavern mice can crawl and hide under). Mice generally must be housed with cage mates for social interaction, generally in non-breeding cages, these will be same-sex littermates weaned at the same time.
Mice may not be weaned prior to 21 days (24 days or later for certain strains or unusually small mice unready for weaning).
Studies that involve injections include a control group who receive equivalent control injections (typically saline and vehicle).
Mice may be euthanized via carbon dioxide up to five to a cage at a time (I've only ever euthanized singly for my experiments) and living mice should not be in the same room at the time. For terminal cardiac puncture, the procedure must be performed under anesthesia (if scientific considerations preclude this, the justification needs to be considered and approved in your protocol before you do it).
My PI and I had a meeting and evaluation of a protocol violation a few years ago. I was using an apparatus which functions as a short, one-off, noninvasive, minimally stressful assessment of anxiety and exploratory behaviors. What I didn't realize that though we had a functionally identical apparatus approved for such use on our protocol, this new apparatus, with a difference in shape that did not meaningfully alter the effects of the assessment on the mice, was not on our protocol (we'd forgotten to add it because it was so similar to the other one). The IACUC, after getting the facts and some discussion, didn't have any lasting issues. But if anything I took away that they are pretty serious about protocol violations, and there are a lot of humane considerations that are either blanket rules or must be approved specifically in a protocol.
With regard to replacing animal studies with other models, we are already required to do so where possible, as well as reduce the number of animals used to the minimum feasible experiment size, as well as refine protocols by substituting less painful and distressing procedures wherever possible. Animal use protocols submitted for approval may be denied if those principles can be applied and are not in the submission. For my own research, I am confident that my experiments cannot be substituted with e.g. cell culture models.
I think that people like you have probably contributed a lot to making the status quo what it is, which in my experience is pretty humane and with a focus on minimizing use of animals where possible and minimizing pain and distress to animals where animal research is valuable. I am not sure you know what the status quo is, because your descriptions do not match what I have observed in my time in animal research.
True, I've never been allowed in an animal lab. As the NIH Guide advises, animal facilities should be windowless, within another building, highly secured, et cetera. [Their section on security is almost as long as their section on Euthanasia - which, incidentally, does not recommend CO2 asphyxiation for neonatal rodents until the "ongoing controversy about its aversive characteristics as an inhalant euthanasia agent" is resolved. Thankfully, "This is an area of active research." Until then, decapitation & cervical dislocation are good humane alternatives.]
I've learned a lot about current practice from talking to people who work at local labs, but more directly from reading their research. I've reviewed, for example, a healthy sampling of the last ten years of [published] animal studies at Sick Kids, a U-Toronto research hospital.
Correct me if Sick Kids is not typical. A bit heavy on the neo-natal studies, of course, including maternal deprivation xps. There may also be more-than-average pain research at Sick Kids, from the influence of its recent Chief of Research, a pain specialist. Unfortunately, if you want to study how painful lionfish venom is, there's no better alternate to injecting a rodent's hind-paw with lionfish venom, then quantifying their "spontaneous pain behavior" as you punctate the plantar surface with von Frey monofilaments. [The pain box is indeed not steel, it's plexiglass - mea culpa.]
Having performed euthanasia on days-old pups, I can tell you why CO2 asphyxiation is not recommended for neonatal rodents: neonatal rodents are resistant to low oxygen conditions and doing so would prolong their suffering - essentially, CO2 euthanasia for pups is very slow suffocation (which is not true for young and adult mice). Decapitation, which I have used, is quick and any pain is very short-lived. Just because *you* find it unaesthetic does not mean it is ill considered or less humane than the alternative you might think is preferable.
I took a quick look at your findings, such as they are and wow, okay, that's what this is. So, most of the methods sections you excerpt seem completely normal to me, and several of them are procedures which do not involve pain or distress to the animal (as opposed to pain or distress which, however minimized and whatever the scientific value, I assume you would object). It seems to me that you simply object to most forms of animal research, and prefer extremely charged language "vivisectors", "gas chambers" to try to induce the same emotional response in your readers. Or just go all out and call it a "demonic death cult". Yeah, you have a conscientious, well-thought-out approach to animal research all right.
Let me be clear: you wrote a manifesto, several "press releases", and apparently harassed research staff (and considered this worth bragging about!) on the basis of objections to research that you do not understand. You do not understand the research methods or why any of these approaches are chosen. You do not understand the research prerogatives, that is, you don't know what the scientific questions involved are or why anyone would consider studying them. And you do not understand the regulations of animal research - apparently, neither the very detailed and involved requirements and restrictions nor the history of their implementation. If this is representative of your academic interests and pursuits in philosophy, you are a hack and a fraud.
Honestly, I didn't expect to write such a harsh response, but your absolutely facile "findings" make it quite clear that you have no idea what you're talking about.
But 'vivisectors' and 'gas chambers' they are. Quite sensibly, these terms provoke an emotional reaction from good people. But call it a CO2 chamber, if you prefer. Re the first term: a vivisector is one who cuts up the living. This cutting is still literal, in your labs, but we can also consider the conceptual cutting denoted by 'analysis' - whose proto-IndoEuropean rootword means to cut, to split. Even these neutral terms, when we dig, can get quite bloody. The putative neutrality is thus a euphemistic glaze for the actual horrors - horrors which you are normalized to, it seems.
It's true that the cutting edge of the new Life Science is often beyond me. The aims of your studies, I don't always understand. But certain words do jump out. I was amazed to find that the term 'sacrifice' is standard in the literature for the terminus event of the research Subject's [vivo] participation. A cute term of art, but hardly value-neutral. Seems to beg the question - sacrifice to What/Whom?
To "Science", to "the Research", to "Big Data", I guess.
I don't want to hijack this thread. I admit this topic is my Carthago Delenda Est. I'd rather not think about it but it does come up everywhere, once you know how to translate the euphemisms. I understand your harsh reaction and don't blame you, and wish you well.
> I wonder if we're ready to talk about the moral contradiction of brutalizing our psychological kin. I mean: these studies are relevant to human Psychology only because the beings being abused in them are like us in morally relevant respects.
Moral doesn't show up in the test tube. The animals are relevant here because taxonomic proximity goes with increased similarity in the (neuro)physiological and psychological similarity, (and because we don't use humans any more for the cruel things (I hope)). The moral thing -- researchers experimenting on themselves -- well, there's only so many things you can do to yourself before you cease to be a proficient researcher.
And one moral consideration: Suffering within all of creation is not zero-sum. The moral calculus must include a factor for insights gained by animal experimentation now will ameliorate other animals' suffering in the future.
Our problem here is that we just don't know the path of minimal investment in suffering.
Also, we have to justify speciesism (why a mouse or ape and not a human).
But there's something perverse about carefully regulating the amount of pain that scientists may cause a small number of mice in order to learn something; yet allowing people to kill mice in the billions every year with brutal mousetraps, or by letting their cats outdoors, or by feeding their pet snakes with mice bought from pet shops for that purpose. It seems to me more like discrimination against scientists than like sincere concern for mice.
I'm casually familiar with how UpToDate, NICE review and synthesize new findings, but have no idea how Wikipedia does it. How do they review literature? Can't anyone edit those pages? I usually trust Wikipedia for basic facts, but don't have a good gauge for its quality in evolving fields.
Also, I think you should post your predictions in Metaculus (or another prediction market when better ones come along). You might even help get researchers more interested in prediction markets.
What about some bio/psycho interaction? For example - initial serotonin elevation dampens amygdala reactivity, but only when the calmed down amygdala meets the world and sees people aren't as bad as it perceived before does the depression start to remit. This will explain the time needed for anti-depressant effect to take place, and maybe some biological findings (such as elevated BDNF) are secondary to effective re-learning and not due to a direct anti-depressant effect. In other words - set and setting matter in anti-depressant treatment too. Browning et al. have an interesting paper where they can predict response in an early stage, depending on altered emotional processing https://www.sciencedirect.com/science/article/pii/S0924977X18319631
supporting the claim that the medication only alters some basic emotional processing property, but that the anti-depressant effect is dependent on meeting the world with different glasses
"Pictured: BDNF binds to TrkB. The IRS confiscates 1/2 of it as taxes, which radicalizes the receptor and makes it join Gab (see footnote 1), where it tweets out an SOS message to the Ras of Ethiopia. But the left wing of the receptor joins the Palestine Liberation Council and moves to California (see footnotes 2+). California has sunshine and good beaches, so you stop feeling depressed."
Where are the footnotes for this? I want to learn more about GAB and the adventures of the Palestine Liberation Council :)
> Also, all these mice studies are great, but in human studies, SSRIs barely work. The best meta-analyses of thousands of depressed patients manage to pick up a small signal, assuming the pharma companies haven’t figured out some way to fake us all out.
I’m extremely confused by both this and the “month-to-take-effect” part. I know well a couple people with depression. For both of them, they used to have pretty bad depression. They’ve been on ADs for years and they’re now basically normal. If they miss even a single pill, however, they consistently go back to seriously depressed for a couple days before returning to normal. Is this something-something adjusted to the medication + placebo effect? That seems not enough to explain the extreme effects.
Generally, I’ve seen that ADs seem to either work well for people or not really work at all (or trying a few might find a successful one). So it’s very strange that metanalyses don’t seem to find an effect on anyone.
Scott casually made mention of nasty "thought loops" that are part of depression:
"The whole network becomes sparser than usual, and dysfunctional thought-loops that thrive in sparse network conditions start taking over."
I'm way over my head with this topic, and maybe this is common knowledge, but I'm very curious about how researchers adjust for the unique ways humans process thought when analyzing results in mice. For example, if, say, a mouse's overblown cortisone levels are relieved with treatment, isn't it possible that that relief could be cemented much more quickly than in a human whose powerful thought processes might play a role in "defending" against dramatic overnight challenges to the ego, superego, etc? Stress manifestation, it seems to me, must play a huge role in personality development -- so it could be something the ego is desperate to hang onto?
I take duloxetine, but for fibromyalgia and other nerve damage issues. It relieves pain and other symptoms by about 50%, but I'm intrigued that it never seemed to affect my state of mind. My thought processes historically have not generally fallen into the "dysfunctional thought-loop" pattern that I recognized in my depressed father. Makes me wonder if I inherited some of his neurological deficiencies but that for some reason they manifest differently (as pain without the thought loops)?
My personal experience makes me skeptical of the idea that depression is a thought/behavior disorder. I have in the past had issues with intrusive negative thoughts, might even describe them as looping, and behavioral compulsions, these well preceded my depression actually. But, well at least for the thought part of that equation, I think I've mostly tamed them. This is a practiced habit that took some time to form. I still have negative thoughts, sometimes irrational ones, but if I decide it's gotten out of hand I can usually break the cycle and think about something else, or perhaps nothing at all, no matter how bad I feel. I do this as well or better than than the average non-depressed person, and have no trouble forming positive/constructive thoughts when I need them. On the other side, well I can't claim full victory there, but certainly my behaviors are overall much healthier than they've been for most of my life. I meet my basic obligations, holding down a job (a career even!), exercising, eating healthily, spending time with my kids, not doing hard drugs, moderating the soft ones. But I am so fucking depressed, far more than I've ever been, to a good approximation my internal experience consists entirely of varying gradations of unpleasantness. For me depression is a feeling, it's guilt, disgust, anger, or even more often just pure undifferentiated dysphoria.
I have a lot of thoughts and questions after reading your generous comment, Dualmindblade. Your description, I think, fits my father's rather severe lifelong depression better than "thought loops."
I still wonder what a mouse would feel given your condition. Without anger, guilt, disgust, etc, its symptoms would be consolidated into a sort of neurological pain, right? (I'm still wondering about the mystery of why mice respond more quickly to antidepressants, but I suppose my theory on the human mind putting up a defense against the meds is not supported by your experience.)
But, also still wondering if I could have inherited some of my father's brain chemistry but the deficiencies have shown up in my body more like the mouse: my main fibro pain is systemic -- typical feeling of burning nerves under the surface and flu-like symptoms -- yet unaccompanied by emotions other than the drive to lie down and rest frequently. Spin-off conditions that are less fleeting (such as connective tissue problems) seem likely to have the same neuropathic etiology.
My late-life revelation is that what ought to have been my main source of energy production (i.e., mitochondrial) has always been deficient, so I've had to learn to live utilizing mostly stress energy, which, eventually, made me sick -- like being allergic to one's own energy. That's my current theory anyway. I would not presume to claim a kinship with severe depression like yours, except that my father's case makes me curious.
So I've heard rumors about the role of the gut in depression and the neurotransmitters that are manufactured in the gut. Disclaimer, disclaimer, I know nothing, etc not a professional. However the SSRIs are usually in pill form taken by mouth. How much of the effect of the SSRIs, whatever size that effect is - how much of that is from the med accumulating literally in the brain, and how much of it is related to a) bloodstream levels affecting gut neurotransmitters or b) whatever amount of SSRI passes through the actual gut/intestines?
"Indeed, a flurry of studies in the past several years indicates that the gut microbiome's importance goes beyond physical health: It is also a key player in the gut-brain connection. In one striking demonstration of the potency of the so-called "microbiome-gut-brain axis," published in Gastroenterology in 2011, Bercik and colleagues gave BALB/c mice, a strain of mice that are typically timid and shy, a cocktail of antibiotics, dramatically changing the composition of their gut bacteria.
"Their behavior completely changed," Bercik says. "They became bold and adventurous."
The antibiotic treatment also boosted levels of brain-derived neurotrophic factor (BDNF) in the hippocampus. This neurochemical promotes neural connections and is an important factor in memory and mood. When the antibiotic regimen was stopped, the animals soon reverted to their usual, cautious selves, and their brain biochemistry also returned to normal."
Substances based on adhesmine (pyridoxine) and sulbutiamine (Arcalion) at dosages above 300mg per day seem to produce good effects in the medium term, after 30 to 60 days, or in a longer period for more severe depressions.
> Neurons are less likely to respond to stimuli by connecting to other neurons.
That sounds like something for feeling dumb, but not as a reason for the bad mood.
There are a lot of papers, that show that depression is a systemic disfunction in cells' methabolism. Every neuron has pretty complex ion machinery, including moving ions through membrane and storing them in places like endoplasmic reticulum and mitochondria.
Both these organelles are involved in depression:
Role of endoplasmic reticulum stress in depression
The reason why it takes months to activate the depression response to SSRI could be that SSRI do not directly fix problems like Endoplasmic Reticulum stress. They could work more profound. For example:
fluoxetine-induced decrease in mitochondrial ATP production results in the emptying of the ER, leading to capacitative calcium entry. Furthermore, Ca2+ quickly accumulated in the mitochondria, leading to mitochondrial Ca2+ overload
And that kind of mechanism of emptying ER (by blocking ATP or by activating ER IP3 receptors via 5-HT2) may lead to normalization of the cell function:
On the other hand, loss of luminal Ca2+ causes ER stress and activates an unfolded protein response, which, depending on the duration and severity of the stress, can reestablish normal ER function or lead to cell death.
ER stress and its XBP1 stress signaling is also linked to the BDNF activity:
The Role of Brain-derived Neurotrophic Factor (BDNF)-induced XBP1 Splicing during Brain Development
Xbp1 was activated in neurites in response to brain-derived neurotrophic factor (BDNF), followed by subsequent translocation of the active Xbp1 into the nucleus. BDNF-dependent neurite outgrowth was significantly attenuated in Xbp1−/- neurons.
Is it intentional that the word "something" appears repeatedly in the first paragraphs of this blog post? It look like either placeholders the author used in a draft and never corrected before posting, or a way to bypass explaining some complicated neurobiological process, or some sort of random error when the article posted. In any case, it undermines credibility and you may want to fix.
I've also seen it used in situations where there's details the speaker doesn't know, as a way of explicitly calling out the gaps in description. (As distinct from the speaker knowing details, but choosing to elide them)
Wait! Doesn't it take a very skilled rodent therapist to determine whether the mouse was depressed in the first place and to evaluate extent of recovery?
> But why are so many monoaminergic substances antidepressants? Where are all the papers saying "we tested this new SSRI, it did a great job inhibiting serotonin reuptake, but there was no antidepressant effect whatsoever"? Surely some substances that are SSRIs don't also interact with this new TrkB receptor domain?
Perhaps the binding site for whatever protein is being inhibitted by these SSRIs is very similar to the newly discovered binding site in the TrkB receptor. If so, then any substances which fits one binding site will also be very likely to fit the other, which would make it very hard to find an SSRI which isn't also doing this TrkB thing.
I was speculating specifically about SSRI as they are the drugs relevant to the newly discovered mechanism. MAOI aren't really relevant to the questions being asked, which amount to "why would all SSRIs interact with this TrkB receptor?" My sollution to this question is to point out that this is a physical system and that these two receptors shouldn't be assumed to be independent. If one compound binds to both receptors, then it seems likely that other compounds would bind to both receptors.
To give you an analogy, these questions from scott are like noticing that one key will work for two different locks and then wondering why you can't find keys that work with one lock but not the other. The fact that one key works for both locks tells you something about the locks, that they must be very similar, which makes it more likely that future keys you find that fit one lock will also fit the other.
There are some TRK inhibitors approved for treatment of cancers driven by TRK fusion (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859818/) . Some of them even are used to treat brain cancer. For example, entrectinib was originally developed as an inhibitor of ALK for the treatment of ALK-driven lung cancer with a twist that it can get to the brain to pursue metastasis their. As the field became overcrowded (https://en.wikipedia.org/wiki/ALK_inhibitor), the developers re-purpused the drug to hit TRK (apparently many ALK inhibitors inhibit TRKA/B/C, and entrectinib was one of such drugs). Finally they got an approval. It's fun to observe how the view on BBB penetration changed from glee (wow, we hit brain mets) to horror (omg, TRK might be important for depression something-something) to optimism (we can treat TRK driven cancers in the brain). Long story short, depression is one of the AEs for entrectinib (https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf) , but it's not reported for the other BBB-penetrating TRK inhbitor larotrectinib (https://ascopubs.org/doi/abs/10.1200/jco.2019.37.15_suppl.2006).
I just wanted to say I love this use of question marks in non-questions. It's probably a known thing but I saw it here for the first time and, as everything with Scott's writing, it was very apt and lucid, easy to move past the initial annoyance jolt. By using it on all three sentences in a paragraph, Scott manages to suppress the inevitable "typo?" response.
It doesn't effect the point that if it takes studies of a zillion people to find an effect for SSRIs in people how come tiny studies can detect an effect in mice, but I'm a bit surprised you've summed up the former as 'SSRIs barely work', given that I thought you were arguing against exactly that reading of the SSRIs-in-humans data here: https://slatestarcodex.com/2018/11/07/ssris-an-update/
Have you changed your mind, or am I wrong in thinking that post is incompatible with 'SSRIs barely work' being a reasonable, helpful summary of the data?
Yeah, sorry, that's confusing. I said "in human studies, SSRIs barely work". I think the studies show them as barely working, but that they work better for real people for the reasons I mentioned there.
Has the number of synapses per neuron in depressed people been measures, and if so how does it compare with the number of synapses per neuron of non-depressed people? Does this vary according to area of the brain?
I wonder whether there is any correlation between synapses and anything else, such as age, job, or IQ? For example, maybe artists have more synapses in the visual cortex, and footballers have more in the areas controlling leg movements.
Speaking as a guy who started graduate school studying TrkB signaling and who now studies accumulation of junk in the lysosome, I think you're safe as houses on both predictions. I don't know what it was (and still is?) about studying TrkB, but I found the literature on it to be unusually prone to really basic mistakes and implausible findings.
As an example of the former, there were LOTS of studies talking about using K252a as a "specific inhibitor of Trk kinases." Which it is--if you consider only receptor tyrosine kinases. There are a number of very important serine/threonine kinases, including phosphorylase kinase and CamKII, which it inhibits at the same concentration. As an example of the latter, the new hotness when I was starting out was the finding, published in Nature, that TrkB directly modulates voltage-gated sodium channels through some non-phosphorylation-based mode of action (the kinetics weren't right for the effects seen to be due to ordinary kinase activity).
Even at the time, this seemed squirrely to me--too fast, too big an effect, and too hard to square with what else was known about TrkB and voltage-gated sodium channels. And, indeed, almost twenty years further on, it is not central to the understanding of the function of that sodium channel and is considered more as an anomaly and probably an artifact than as a central finding the field (see discussion here https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996523/ for an example).
I'll join you at 95%+ that this turns out to be the same.
Are there any direct interactions between serotonin and TrkB? I'm assuming that would have been picked up long ago, but Scott doesn't list it as one of their controls for the new binding site.
Enjoyable read. However, there are other, non serotonin related, methods of achieving antidepressant effects (ketamine, exercise, socialization, psilocybin, MDMA, etc.). Therefore, I don’t think you can hang your hat on serotonin being a necessary player. I may have missed something! Really appreciate your insight though and I hope I get a response back!!!
The paper is titled "Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects" with DOI:10.1093/ijnp/pyac075
The main conclusions that are relevant here are:
* ketanserin (a 5HT2A antagonist) can be given 1H *after* LSD and will completely remove subjective effets of the intoxication.
* mixing ketanserin and LSD shows no psychological impairement but does not reduce LSD's spike in BDNF levels.
IMO this has important implications on how we view 5HT2A and paves the way to new research.
Ooh, I love the new predictions at the bottom in the nifty boxes! Also, I just want to say how much I appreciate you being back. I get genuinely happy every time I see there's something new to read, because I know it's something worth reading and is absolutely thought-provoking. Thanks so much, Scott!
Seconding this, I love that this is a thing now. I updated my dark theme to add CSS for them: https://userstyles.org/styles/196568/arcane-old-texts
I'm already regretting my predictions on this one - after thinking about it more, I ought to be at least 97% sure of the second one - but I don't have good norms in place for deciding when I can edit predictions, so I'll just mention it here.
Considering the... lugubrious nature of the FDA (Not a bad thing!), and the long pipeline that drugs have to take, I would put it around 99.9% for me. Only mitigating factor I can think of is that SSRIs have been around long enough that I'm sure pharma companies are licking their chops at being able to pioneer a brand new method of action in marketing to doctors. And this is all assuming the effect is real!
Second note: Love the wit on the caption on the picture. I have no idea how you write it, or how you wrote Unsong. You're a wizard.
No, just a former medical student. This is the only way anyone ever passes medical school. See eg https://www.youtube.com/watch?v=EiKg08WoKPM
On the topic of editing predictions: I would find it *most* compelling if predictions were mutable until some change in material conditions or in availability of information occurred. In particular, why not let comments influence them for a few days (perhaps with notes of adjustments)?
Authorial opinion modulated by community opinion a la Tedlow would produce the most interesting bets, imo.
imo it's entirely reasonable to update predictions w some kind of timestamped changelog. Just add the revision below with your new reasoning (& probably only use it for ~relatively timely updates, e.g. w/i a day or week of posting)
Maybe you should consider writing predictions as ratios instead of as percentages. It makes it eaasier to make more exteme predictions when necessary, e.g. 1:30 vs 1:20.
Editing predictions is bad, updating them is always good. Even if the extra evidence is putting in more thought.
Just add an "Edit [date]: ..." below.
Is NICE this NICE? https://www.nice.org.uk/news/nice-newsletters-and-alerts
Yes.
Good thing it isn't this NICE: https://www.goodreads.com/book/show/100933.That_Hideous_Strength
I wonder if duration of discontinuation syndrome sheds any light on the long buildup claim. Looks like the standard answer is that brain zaps last a few weeks tops, but I seem to recall them lasting months, and I see other reports of that when I dig beneath the surface. Seems like something that could easily be underestimated.
> Also, all these mice studies are great, but in human studies, SSRIs barely work. The best meta-analyses of thousands of depressed patients manage to pick up a small signal, assuming the pharma companies haven’t figured out some way to fake us all out.
This is the part that bugs me the most. How can you claim to have discovered the mechanism behind an effect that, as far as I can tell, may not even exist?
It's well know that compounds with basic amines (e.g. amantadine, monamines, etc) accumulate in lysosomes. The basic mechanism is simple: uncharged molecules generally pass through cell membranes more easily than charged molecules. At physiological pH a small fraction of basic amines (~0.1%) will be uncharged. In lysosomes however, which are 2-3 pH units lower, only 0.001-0.0001% will be uncharged.
In a slightly simplified scenario where only uncharged compounds can pass through membranes, there will be roughly 100-1000x more compounds capable of entering a lysosome than of exiting one at any given moment. This essentially means lysosomes are sinks for basic compounds.
I'm not sure how this would affect overall brain accumulation, especially over week-long periods, but it does make the AD accumulation bit seem a bit more plausible.
Scott, how open are you to giving scientific talks about these issues in a university setting? (Either in person or more likely Zoom). I organize the lab meetings for my neuroscience lab at Hebrew University (Jerusalem) and we'd be happy to get your perspective. (I've recently been working on models/ideas that involve BDNF and plasticity so this is especially interesting to me).
I don't actually know anything about this, I'm making it up as I go along with a lot of help from Google Scholar. Also in general I don't give talks, sorry.
There are quite a few sentences that end with question marks without much good reason in this piece? It's the first time I've noticed that in Scott's writing?
I noticed that too. It's kind of a cute way to write though, so I'm not really complaining.
This is a very confusing topic; he's allowed to use a lot of question marks.
see https://slatestarcodex.com/2016/02/20/writing-advice/. It's a useful way share uncertainty/confusion with the reader. "Defend your flow of ideas at all costs. This might sound paradoxical after section 2, which was about how breaking flows is great. It is kind of paradoxical, and it is sort of hard to explain, but it’s the difference between 'exciting' and 'horrible'."
Yeah, I think instead of the technically grammatically prescribed "question marks are used to mark questions", he's using question marks to mark the upward inflection of spoken speech that we use when we're unsure about what we're talking about, even when the statement isn't grammatically a question.
It reminds me of Matt Levine's writing!
The "something something" remarks read (to me anyway) like he is cynical about findings from certain molecular biology experiments. Many of which are routine in academic and commercial labs where this kind of research is conducted. They represent the kind of hard, painstaking scientific work that must be done (and has been done) to understand molecular function in order to develop effective drugs. To then say - "I'm not a cellular biologist or a biochemist, so I can't comment on most of the high-tech methods used in this paper." - begs a different question: So why did you?
OTOH, I found it a minor refreshment from the usual "genes something something genes."
How *do* you figure out whether a mouse is depressed? (if our animal models were cetacean rather than rodentine, would our inventories find porpoises more depressed than dolphins?)
You throw it into the water and check when it gives up treading water and decides it would rather drown.
I'm not even kidding - https://en.wikipedia.org/wiki/Behavioural_despair_test .
For a more thorough discussion with, on average, less animal abuse
- https://cdn.intechopen.com/pdfs/22663/InTech-Mouse_models_of_depression.pdf has an overview.
The system is inherently abusive. I wonder how Björkholm et al correct for the baseline fear & anxiety of animals being caged, stabbed with needles, and [ultimately] decapitated or mass-gassed? [or stabbed yet again, intracardially.]
"Cortisone levels rise in monkeys watching other monkeys being restrained for blood collection. Blood pressure and heart rates elevate in rats watching other rats being decapitated." [Aysha Akhtar, The Flaws and Human Harms of Animal Experimentation. Cambridge Quarterly of Healthcare Ethics, 24[4] [2015], 407–419.]
I wonder if we're ready to talk about the moral contradiction of brutalizing our psychological kin. I mean: these studies are relevant to human Psychology only because the beings being abused in them are like us in morally relevant respects. I.e. maternal deprivation experiments on rats work because rat mothers and pups love each other. Or something analogous enough to your "love" to be data-relevant.
On the other hand, these studies risk being irrelevant because they can't correct for all the inherent abuses. I.e. Almost all animal studies are maternal deprivation studies, unacknowledged.
To be fair, at least within the EU the well-being of lab animals in public institutions at least has massively improved and you actually need to explain the ethics of your experiment, the ways you'll minimize harm to the animals etc. before they let you stab them. I spoke to some people involved with our local medical university's animal research and they seemed way more ethical than the average meat eater, tbh.
What's going on behind closed doors of corporate R&D is, I imagine, not as pleasant.
I have hope in the rise of non-animal models, where the EU seems to be ahead of N.America, predictably. Non-animal models [The Johns Hopkins Center for Alternatives to Animal Testing is a trove of info on this & related] may take over Toxicology in the coming decades, but it's hard to see how Psychopathology could do the same.
Nice people, yes. Animal Care Ethics Committees, yes. The banality of Civilization's evil - it's mainly "decent" people, conscientious in their way, who do the City's monstrous work.
Hard to say things have improved for animals when our manipulations of them have only deepened since the days of Pavlov. Their steel cages might be a tad bigger, but we genetically cage & cripple them now. Our repertoire of sadism only expands, yet the sadism is hard to spot at the personal level - I too have spoken with many intelligent & sensitive animal researchers.
And hard to separate College from Corporate lab, when the former are used to publicly fund proprietary gains for that latter, and the profs consult happily for Pfizer et al.
I can only speak from my own experience at my institution (Georgetown University) and with the model organism I have used (mouse). As far as I am aware, much of this is similar for rats.
Mouse cages are plastic, not steel, and aside from bedding, food and water ad lib., they typically feature an enrichment toy (e.g. a plastic cavern mice can crawl and hide under). Mice generally must be housed with cage mates for social interaction, generally in non-breeding cages, these will be same-sex littermates weaned at the same time.
Mice may not be weaned prior to 21 days (24 days or later for certain strains or unusually small mice unready for weaning).
Studies that involve injections include a control group who receive equivalent control injections (typically saline and vehicle).
Mice may be euthanized via carbon dioxide up to five to a cage at a time (I've only ever euthanized singly for my experiments) and living mice should not be in the same room at the time. For terminal cardiac puncture, the procedure must be performed under anesthesia (if scientific considerations preclude this, the justification needs to be considered and approved in your protocol before you do it).
My PI and I had a meeting and evaluation of a protocol violation a few years ago. I was using an apparatus which functions as a short, one-off, noninvasive, minimally stressful assessment of anxiety and exploratory behaviors. What I didn't realize that though we had a functionally identical apparatus approved for such use on our protocol, this new apparatus, with a difference in shape that did not meaningfully alter the effects of the assessment on the mice, was not on our protocol (we'd forgotten to add it because it was so similar to the other one). The IACUC, after getting the facts and some discussion, didn't have any lasting issues. But if anything I took away that they are pretty serious about protocol violations, and there are a lot of humane considerations that are either blanket rules or must be approved specifically in a protocol.
With regard to replacing animal studies with other models, we are already required to do so where possible, as well as reduce the number of animals used to the minimum feasible experiment size, as well as refine protocols by substituting less painful and distressing procedures wherever possible. Animal use protocols submitted for approval may be denied if those principles can be applied and are not in the submission. For my own research, I am confident that my experiments cannot be substituted with e.g. cell culture models.
I think that people like you have probably contributed a lot to making the status quo what it is, which in my experience is pretty humane and with a focus on minimizing use of animals where possible and minimizing pain and distress to animals where animal research is valuable. I am not sure you know what the status quo is, because your descriptions do not match what I have observed in my time in animal research.
True, I've never been allowed in an animal lab. As the NIH Guide advises, animal facilities should be windowless, within another building, highly secured, et cetera. [Their section on security is almost as long as their section on Euthanasia - which, incidentally, does not recommend CO2 asphyxiation for neonatal rodents until the "ongoing controversy about its aversive characteristics as an inhalant euthanasia agent" is resolved. Thankfully, "This is an area of active research." Until then, decapitation & cervical dislocation are good humane alternatives.]
I've learned a lot about current practice from talking to people who work at local labs, but more directly from reading their research. I've reviewed, for example, a healthy sampling of the last ten years of [published] animal studies at Sick Kids, a U-Toronto research hospital.
[I excerpted some of my findings here: https://philpapers.org/rec/BALVS-2]
Correct me if Sick Kids is not typical. A bit heavy on the neo-natal studies, of course, including maternal deprivation xps. There may also be more-than-average pain research at Sick Kids, from the influence of its recent Chief of Research, a pain specialist. Unfortunately, if you want to study how painful lionfish venom is, there's no better alternate to injecting a rodent's hind-paw with lionfish venom, then quantifying their "spontaneous pain behavior" as you punctate the plantar surface with von Frey monofilaments. [The pain box is indeed not steel, it's plexiglass - mea culpa.]
Having performed euthanasia on days-old pups, I can tell you why CO2 asphyxiation is not recommended for neonatal rodents: neonatal rodents are resistant to low oxygen conditions and doing so would prolong their suffering - essentially, CO2 euthanasia for pups is very slow suffocation (which is not true for young and adult mice). Decapitation, which I have used, is quick and any pain is very short-lived. Just because *you* find it unaesthetic does not mean it is ill considered or less humane than the alternative you might think is preferable.
I took a quick look at your findings, such as they are and wow, okay, that's what this is. So, most of the methods sections you excerpt seem completely normal to me, and several of them are procedures which do not involve pain or distress to the animal (as opposed to pain or distress which, however minimized and whatever the scientific value, I assume you would object). It seems to me that you simply object to most forms of animal research, and prefer extremely charged language "vivisectors", "gas chambers" to try to induce the same emotional response in your readers. Or just go all out and call it a "demonic death cult". Yeah, you have a conscientious, well-thought-out approach to animal research all right.
Let me be clear: you wrote a manifesto, several "press releases", and apparently harassed research staff (and considered this worth bragging about!) on the basis of objections to research that you do not understand. You do not understand the research methods or why any of these approaches are chosen. You do not understand the research prerogatives, that is, you don't know what the scientific questions involved are or why anyone would consider studying them. And you do not understand the regulations of animal research - apparently, neither the very detailed and involved requirements and restrictions nor the history of their implementation. If this is representative of your academic interests and pursuits in philosophy, you are a hack and a fraud.
Honestly, I didn't expect to write such a harsh response, but your absolutely facile "findings" make it quite clear that you have no idea what you're talking about.
But 'vivisectors' and 'gas chambers' they are. Quite sensibly, these terms provoke an emotional reaction from good people. But call it a CO2 chamber, if you prefer. Re the first term: a vivisector is one who cuts up the living. This cutting is still literal, in your labs, but we can also consider the conceptual cutting denoted by 'analysis' - whose proto-IndoEuropean rootword means to cut, to split. Even these neutral terms, when we dig, can get quite bloody. The putative neutrality is thus a euphemistic glaze for the actual horrors - horrors which you are normalized to, it seems.
It's true that the cutting edge of the new Life Science is often beyond me. The aims of your studies, I don't always understand. But certain words do jump out. I was amazed to find that the term 'sacrifice' is standard in the literature for the terminus event of the research Subject's [vivo] participation. A cute term of art, but hardly value-neutral. Seems to beg the question - sacrifice to What/Whom?
To "Science", to "the Research", to "Big Data", I guess.
I don't want to hijack this thread. I admit this topic is my Carthago Delenda Est. I'd rather not think about it but it does come up everywhere, once you know how to translate the euphemisms. I understand your harsh reaction and don't blame you, and wish you well.
> I wonder if we're ready to talk about the moral contradiction of brutalizing our psychological kin. I mean: these studies are relevant to human Psychology only because the beings being abused in them are like us in morally relevant respects.
Moral doesn't show up in the test tube. The animals are relevant here because taxonomic proximity goes with increased similarity in the (neuro)physiological and psychological similarity, (and because we don't use humans any more for the cruel things (I hope)). The moral thing -- researchers experimenting on themselves -- well, there's only so many things you can do to yourself before you cease to be a proficient researcher.
And one moral consideration: Suffering within all of creation is not zero-sum. The moral calculus must include a factor for insights gained by animal experimentation now will ameliorate other animals' suffering in the future.
Our problem here is that we just don't know the path of minimal investment in suffering.
Also, we have to justify speciesism (why a mouse or ape and not a human).
But there's something perverse about carefully regulating the amount of pain that scientists may cause a small number of mice in order to learn something; yet allowing people to kill mice in the billions every year with brutal mousetraps, or by letting their cats outdoors, or by feeding their pet snakes with mice bought from pet shops for that purpose. It seems to me more like discrimination against scientists than like sincere concern for mice.
I'm casually familiar with how UpToDate, NICE review and synthesize new findings, but have no idea how Wikipedia does it. How do they review literature? Can't anyone edit those pages? I usually trust Wikipedia for basic facts, but don't have a good gauge for its quality in evolving fields.
Also, I think you should post your predictions in Metaculus (or another prediction market when better ones come along). You might even help get researchers more interested in prediction markets.
What about some bio/psycho interaction? For example - initial serotonin elevation dampens amygdala reactivity, but only when the calmed down amygdala meets the world and sees people aren't as bad as it perceived before does the depression start to remit. This will explain the time needed for anti-depressant effect to take place, and maybe some biological findings (such as elevated BDNF) are secondary to effective re-learning and not due to a direct anti-depressant effect. In other words - set and setting matter in anti-depressant treatment too. Browning et al. have an interesting paper where they can predict response in an early stage, depending on altered emotional processing https://www.sciencedirect.com/science/article/pii/S0924977X18319631
supporting the claim that the medication only alters some basic emotional processing property, but that the anti-depressant effect is dependent on meeting the world with different glasses
This echoes the recommendation to use the two-pronged approach of psychotherapy (or -analysis) combined with antidepressants.
Lovely, mnemonic in the caption!
[epistemic status: cheerfully ignorant conjecture, like most of what I believe, but don't really understand]
BDNF binds to cholesterol? Cool.
More evidence for the "cholesterol is good, you haters!"-side.
That side appears less crazy to me than "cholesterol is bad for you", but I have a strong contrarian bias.
[or rather I just think, that majority belief is usually insane group-think, since we live in the insane timeline]
Can explain those findings better:
https://www.psychologytoday.com/us/blog/the-breakthrough-depression-solution/201106/low-cholesterol-and-its-psychological-effects
I think the carnivore diet has been claimed to have antidepressant effects, too.
Not a great signal though, too radically different in general, too few people doing it.
https://meatrx.com/category/success-stories/depression/
Is there any other "high cholesterol"-diet to look at, for figuring out whether it's suitable as an intervention?
Eat all the bacon and eggs they have and die happy of a heart attack.
Good deal, right?
"Pictured: BDNF binds to TrkB. The IRS confiscates 1/2 of it as taxes, which radicalizes the receptor and makes it join Gab (see footnote 1), where it tweets out an SOS message to the Ras of Ethiopia. But the left wing of the receptor joins the Palestine Liberation Council and moves to California (see footnotes 2+). California has sunshine and good beaches, so you stop feeling depressed."
Where are the footnotes for this? I want to learn more about GAB and the adventures of the Palestine Liberation Council :)
> Also, all these mice studies are great, but in human studies, SSRIs barely work. The best meta-analyses of thousands of depressed patients manage to pick up a small signal, assuming the pharma companies haven’t figured out some way to fake us all out.
I’m extremely confused by both this and the “month-to-take-effect” part. I know well a couple people with depression. For both of them, they used to have pretty bad depression. They’ve been on ADs for years and they’re now basically normal. If they miss even a single pill, however, they consistently go back to seriously depressed for a couple days before returning to normal. Is this something-something adjusted to the medication + placebo effect? That seems not enough to explain the extreme effects.
Generally, I’ve seen that ADs seem to either work well for people or not really work at all (or trying a few might find a successful one). So it’s very strange that metanalyses don’t seem to find an effect on anyone.
Scott casually made mention of nasty "thought loops" that are part of depression:
"The whole network becomes sparser than usual, and dysfunctional thought-loops that thrive in sparse network conditions start taking over."
I'm way over my head with this topic, and maybe this is common knowledge, but I'm very curious about how researchers adjust for the unique ways humans process thought when analyzing results in mice. For example, if, say, a mouse's overblown cortisone levels are relieved with treatment, isn't it possible that that relief could be cemented much more quickly than in a human whose powerful thought processes might play a role in "defending" against dramatic overnight challenges to the ego, superego, etc? Stress manifestation, it seems to me, must play a huge role in personality development -- so it could be something the ego is desperate to hang onto?
I take duloxetine, but for fibromyalgia and other nerve damage issues. It relieves pain and other symptoms by about 50%, but I'm intrigued that it never seemed to affect my state of mind. My thought processes historically have not generally fallen into the "dysfunctional thought-loop" pattern that I recognized in my depressed father. Makes me wonder if I inherited some of his neurological deficiencies but that for some reason they manifest differently (as pain without the thought loops)?
My personal experience makes me skeptical of the idea that depression is a thought/behavior disorder. I have in the past had issues with intrusive negative thoughts, might even describe them as looping, and behavioral compulsions, these well preceded my depression actually. But, well at least for the thought part of that equation, I think I've mostly tamed them. This is a practiced habit that took some time to form. I still have negative thoughts, sometimes irrational ones, but if I decide it's gotten out of hand I can usually break the cycle and think about something else, or perhaps nothing at all, no matter how bad I feel. I do this as well or better than than the average non-depressed person, and have no trouble forming positive/constructive thoughts when I need them. On the other side, well I can't claim full victory there, but certainly my behaviors are overall much healthier than they've been for most of my life. I meet my basic obligations, holding down a job (a career even!), exercising, eating healthily, spending time with my kids, not doing hard drugs, moderating the soft ones. But I am so fucking depressed, far more than I've ever been, to a good approximation my internal experience consists entirely of varying gradations of unpleasantness. For me depression is a feeling, it's guilt, disgust, anger, or even more often just pure undifferentiated dysphoria.
I have a lot of thoughts and questions after reading your generous comment, Dualmindblade. Your description, I think, fits my father's rather severe lifelong depression better than "thought loops."
I still wonder what a mouse would feel given your condition. Without anger, guilt, disgust, etc, its symptoms would be consolidated into a sort of neurological pain, right? (I'm still wondering about the mystery of why mice respond more quickly to antidepressants, but I suppose my theory on the human mind putting up a defense against the meds is not supported by your experience.)
But, also still wondering if I could have inherited some of my father's brain chemistry but the deficiencies have shown up in my body more like the mouse: my main fibro pain is systemic -- typical feeling of burning nerves under the surface and flu-like symptoms -- yet unaccompanied by emotions other than the drive to lie down and rest frequently. Spin-off conditions that are less fleeting (such as connective tissue problems) seem likely to have the same neuropathic etiology.
My late-life revelation is that what ought to have been my main source of energy production (i.e., mitochondrial) has always been deficient, so I've had to learn to live utilizing mostly stress energy, which, eventually, made me sick -- like being allergic to one's own energy. That's my current theory anyway. I would not presume to claim a kinship with severe depression like yours, except that my father's case makes me curious.
Something to do with antidepressants' sensitivity to sudden withdrawal and rebound effects?
Even if the average effect is small, that might be because they do nothing for most people and work a lot for a relatively small minority.
So I've heard rumors about the role of the gut in depression and the neurotransmitters that are manufactured in the gut. Disclaimer, disclaimer, I know nothing, etc not a professional. However the SSRIs are usually in pill form taken by mouth. How much of the effect of the SSRIs, whatever size that effect is - how much of that is from the med accumulating literally in the brain, and how much of it is related to a) bloodstream levels affecting gut neurotransmitters or b) whatever amount of SSRI passes through the actual gut/intestines?
Maybe somebody knows or knows where to look.
"Indeed, a flurry of studies in the past several years indicates that the gut microbiome's importance goes beyond physical health: It is also a key player in the gut-brain connection. In one striking demonstration of the potency of the so-called "microbiome-gut-brain axis," published in Gastroenterology in 2011, Bercik and colleagues gave BALB/c mice, a strain of mice that are typically timid and shy, a cocktail of antibiotics, dramatically changing the composition of their gut bacteria.
"Their behavior completely changed," Bercik says. "They became bold and adventurous."
The antibiotic treatment also boosted levels of brain-derived neurotrophic factor (BDNF) in the hippocampus. This neurochemical promotes neural connections and is an important factor in memory and mood. When the antibiotic regimen was stopped, the animals soon reverted to their usual, cautious selves, and their brain biochemistry also returned to normal."
-https://www.apa.org/monitor/2012/09/gut-feeling
this substack is habitforming.
Substances based on adhesmine (pyridoxine) and sulbutiamine (Arcalion) at dosages above 300mg per day seem to produce good effects in the medium term, after 30 to 60 days, or in a longer period for more severe depressions.
> Neurons are less likely to respond to stimuli by connecting to other neurons.
That sounds like something for feeling dumb, but not as a reason for the bad mood.
There are a lot of papers, that show that depression is a systemic disfunction in cells' methabolism. Every neuron has pretty complex ion machinery, including moving ions through membrane and storing them in places like endoplasmic reticulum and mitochondria.
Both these organelles are involved in depression:
Role of endoplasmic reticulum stress in depression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854536/
Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997778/#__sec2title
The reason why it takes months to activate the depression response to SSRI could be that SSRI do not directly fix problems like Endoplasmic Reticulum stress. They could work more profound. For example:
fluoxetine-induced decrease in mitochondrial ATP production results in the emptying of the ER, leading to capacitative calcium entry. Furthermore, Ca2+ quickly accumulated in the mitochondria, leading to mitochondrial Ca2+ overload
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356874/
And that kind of mechanism of emptying ER (by blocking ATP or by activating ER IP3 receptors via 5-HT2) may lead to normalization of the cell function:
On the other hand, loss of luminal Ca2+ causes ER stress and activates an unfolded protein response, which, depending on the duration and severity of the stress, can reestablish normal ER function or lead to cell death.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098671/
ER stress and its XBP1 stress signaling is also linked to the BDNF activity:
The Role of Brain-derived Neurotrophic Factor (BDNF)-induced XBP1 Splicing during Brain Development
Xbp1 was activated in neurites in response to brain-derived neurotrophic factor (BDNF), followed by subsequent translocation of the active Xbp1 into the nucleus. BDNF-dependent neurite outgrowth was significantly attenuated in Xbp1−/- neurons.
https://www.jbc.org/article/S0021-9258(20)54505-5/fulltext
This is interesting. Thank you.
Is it intentional that the word "something" appears repeatedly in the first paragraphs of this blog post? It look like either placeholders the author used in a draft and never corrected before posting, or a way to bypass explaining some complicated neurobiological process, or some sort of random error when the article posted. In any case, it undermines credibility and you may want to fix.
"Is it intentional that the word "something" appears repeatedly in the first paragraphs of this blog post?"
Yes, the intention is to convey a joke. "something something" is a known literary device and real-life phatic expression: https://www.urbandictionary.com/define.php?term=something%20something
It is used for all manner of "not worth mentioning/not wishing to be more explicit" utterances: https://en.wiktionary.org/wiki/something-something
(This ends today's "Conversational English As She Is Wrote" lesson).
I've also seen it used in situations where there's details the speaker doesn't know, as a way of explicitly calling out the gaps in description. (As distinct from the speaker knowing details, but choosing to elide them)
Wait! Doesn't it take a very skilled rodent therapist to determine whether the mouse was depressed in the first place and to evaluate extent of recovery?
> But why are so many monoaminergic substances antidepressants? Where are all the papers saying "we tested this new SSRI, it did a great job inhibiting serotonin reuptake, but there was no antidepressant effect whatsoever"? Surely some substances that are SSRIs don't also interact with this new TrkB receptor domain?
Perhaps the binding site for whatever protein is being inhibitted by these SSRIs is very similar to the newly discovered binding site in the TrkB receptor. If so, then any substances which fits one binding site will also be very likely to fit the other, which would make it very hard to find an SSRI which isn't also doing this TrkB thing.
MAO inhibitors are effective antidepressants too, but they have structure and chemical mechanism of action different from SSRI.
I was speculating specifically about SSRI as they are the drugs relevant to the newly discovered mechanism. MAOI aren't really relevant to the questions being asked, which amount to "why would all SSRIs interact with this TrkB receptor?" My sollution to this question is to point out that this is a physical system and that these two receptors shouldn't be assumed to be independent. If one compound binds to both receptors, then it seems likely that other compounds would bind to both receptors.
To give you an analogy, these questions from scott are like noticing that one key will work for two different locks and then wondering why you can't find keys that work with one lock but not the other. The fact that one key works for both locks tells you something about the locks, that they must be very similar, which makes it more likely that future keys you find that fit one lock will also fit the other.
There are some TRK inhibitors approved for treatment of cancers driven by TRK fusion (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859818/) . Some of them even are used to treat brain cancer. For example, entrectinib was originally developed as an inhibitor of ALK for the treatment of ALK-driven lung cancer with a twist that it can get to the brain to pursue metastasis their. As the field became overcrowded (https://en.wikipedia.org/wiki/ALK_inhibitor), the developers re-purpused the drug to hit TRK (apparently many ALK inhibitors inhibit TRKA/B/C, and entrectinib was one of such drugs). Finally they got an approval. It's fun to observe how the view on BBB penetration changed from glee (wow, we hit brain mets) to horror (omg, TRK might be important for depression something-something) to optimism (we can treat TRK driven cancers in the brain). Long story short, depression is one of the AEs for entrectinib (https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf) , but it's not reported for the other BBB-penetrating TRK inhbitor larotrectinib (https://ascopubs.org/doi/abs/10.1200/jco.2019.37.15_suppl.2006).
I just wanted to say I love this use of question marks in non-questions. It's probably a known thing but I saw it here for the first time and, as everything with Scott's writing, it was very apt and lucid, easy to move past the initial annoyance jolt. By using it on all three sentences in a paragraph, Scott manages to suppress the inevitable "typo?" response.
It doesn't effect the point that if it takes studies of a zillion people to find an effect for SSRIs in people how come tiny studies can detect an effect in mice, but I'm a bit surprised you've summed up the former as 'SSRIs barely work', given that I thought you were arguing against exactly that reading of the SSRIs-in-humans data here: https://slatestarcodex.com/2018/11/07/ssris-an-update/
Have you changed your mind, or am I wrong in thinking that post is incompatible with 'SSRIs barely work' being a reasonable, helpful summary of the data?
Yeah, sorry, that's confusing. I said "in human studies, SSRIs barely work". I think the studies show them as barely working, but that they work better for real people for the reasons I mentioned there.
Has the number of synapses per neuron in depressed people been measures, and if so how does it compare with the number of synapses per neuron of non-depressed people? Does this vary according to area of the brain?
I wonder whether there is any correlation between synapses and anything else, such as age, job, or IQ? For example, maybe artists have more synapses in the visual cortex, and footballers have more in the areas controlling leg movements.
Speaking as a guy who started graduate school studying TrkB signaling and who now studies accumulation of junk in the lysosome, I think you're safe as houses on both predictions. I don't know what it was (and still is?) about studying TrkB, but I found the literature on it to be unusually prone to really basic mistakes and implausible findings.
As an example of the former, there were LOTS of studies talking about using K252a as a "specific inhibitor of Trk kinases." Which it is--if you consider only receptor tyrosine kinases. There are a number of very important serine/threonine kinases, including phosphorylase kinase and CamKII, which it inhibits at the same concentration. As an example of the latter, the new hotness when I was starting out was the finding, published in Nature, that TrkB directly modulates voltage-gated sodium channels through some non-phosphorylation-based mode of action (the kinetics weren't right for the effects seen to be due to ordinary kinase activity).
https://pubmed.ncbi.nlm.nih.gov/12384689/
Even at the time, this seemed squirrely to me--too fast, too big an effect, and too hard to square with what else was known about TrkB and voltage-gated sodium channels. And, indeed, almost twenty years further on, it is not central to the understanding of the function of that sodium channel and is considered more as an anomaly and probably an artifact than as a central finding the field (see discussion here https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996523/ for an example).
I'll join you at 95%+ that this turns out to be the same.
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Are there any direct interactions between serotonin and TrkB? I'm assuming that would have been picked up long ago, but Scott doesn't list it as one of their controls for the new binding site.
https://en.wikipedia.org/wiki/N-Acetylserotonin
Thanks, this is interesting.
Enjoyable read. However, there are other, non serotonin related, methods of achieving antidepressant effects (ketamine, exercise, socialization, psilocybin, MDMA, etc.). Therefore, I don’t think you can hang your hat on serotonin being a necessary player. I may have missed something! Really appreciate your insight though and I hope I get a response back!!!
Just reporting from a 2022 paper :
The paper is titled "Ketanserin reverses the acute response to LSD in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects" with DOI:10.1093/ijnp/pyac075
The main conclusions that are relevant here are:
* ketanserin (a 5HT2A antagonist) can be given 1H *after* LSD and will completely remove subjective effets of the intoxication.
* mixing ketanserin and LSD shows no psychological impairement but does not reduce LSD's spike in BDNF levels.
IMO this has important implications on how we view 5HT2A and paves the way to new research.