The Vision Of Vilazodone And Vortioxetine


One of psychiatry’s many embarrassments is how many of our drugs get discovered by accident. They come from random plants or shiny rocks or stuff Alexander Shulgin invented to get high.

But every so often, somebody tries to do things the proper way. Go over decades of research into what makes psychiatric drugs work and how they could work better. Figure out the hypothetical properties of the ideal psych drug. Figure out a molecule that matches those properties. Synthesize it and see what happens. This was the vision of vortioxetine and vilazodone, two antidepressants from the early 2010s. They were approved by the FDA, sent to market, and prescribed to millions of people. Now it’s been enough time to look back and give them a fair evaluation. And…

…and it’s been a good reminder of why we don’t usually do this.

Enough data has come in to be pretty sure that vortioxetine and vilazodone, while effective antidepressants, are no better than the earlier medications they sought to replace. I want to try going over the science that led pharmaceutical companies to think these two drugs might be revolutionary, and then speculate on why they weren’t. I’m limited in this by my total failure to understand several important pieces of the pathways involved, so I’ll explain the parts I get, and list the parts I don’t in the hopes that someone clears them up in the comments.


SSRIs take about a month to work. This is surprising, because they start increasing serotonin immediately. If higher serotonin is associated with improved mood, why the delay?

Most research focuses on presynaptic 5-HT1A autoreceptors, which detect and adjust the amount of serotonin being released in order to maintain homeostasis. If that sounds clear as mud to you, well, it did to me too the first twenty times I heard it. Here’s the analogy which eventually worked for me:

Imagine you’re a salesperson who teleconferences with customers all day. You’re bad at projecting your voice – sometimes it’s too soft, sometimes too loud. Your boss tells you the right voice level for sales is 60 decibels. So you put an audiometer on your desk that measures how many decibels your voice is. It displays an up arrow, down arrow, or smiley face, telling you that you’re being too quiet, loud, or just right.

The audiometer is presynaptic (it’s on your side of the teleconference, not your customer’s side). It’s an autoreceptor, not a heteroreceptor (you’re using it to measure yourself, not to measure anything else). And you’re using it to maintain homeostasis (to keep your voice at 60 dB).

Suppose you take a medication that stimulates your larynx and makes your voice naturally louder. As long as your audiometer’s working, that medication will have no effect. Your voice will naturally be louder, but that means you’ll see the down arrow on your audiometer more often, you’ll speak with less force, and the less force and louder voice will cancel out and keep you at 60 dB. No change.

This is what happens with antidepressants. The antidepressant increases serotonin levels (ie sends a louder signal). But if the presynaptic 5-HT1A autoreceptors are intact, they tell the cells that the signal is too loud and they should release less serotonin. So they do, and now we’re back where we started – ie depressed.

(Why don’t the autoreceptors notice the original problem – that you have too little serotonin and are depressed – and work their magic there? Not sure. Maybe depression affects whatever sets the autoreceptors, and causes them to be set too low? Maybe the problem is with reception, not transmission? Maybe you have the right amount of serotonin, but you want excessive amounts of serotonin because that would fix a problem somewhere else? Maybe you should have paid extra for the premium model of presynaptic autoreceptor?)

So how come antidepressants work after a month? The only explanation I’ve heard is that the autoreceptors get “saturated”, which is a pretty nonspecific term. I think it means that there’s a second negative feedback loop controlling the first negative feedback loop – the cell notices there is way more autoreceptor activity than expected and assumes it is producing too many autoreceptors. Over the course of a month, it stops producing more autoreceptors, the existing autoreceptors gradually degrade, and presynaptic autoreception stops being a problem. In our salesperson analogy, after a while you notice that your audiometer doesn’t match your own perception of how much effort you’re putting into speaking – no matter how quietly you feel like you’re whispering, the audiometer just keeps saying you’re yelling very loud. Eventually you declare it defective, throw it out, and just speak naturally. Now the larynx-stimulating medication can make your voice louder.

In the late ’90s, some scientists wondered – what happens if you just block the 5-HT1A autoreceptors directly? At the very least, seems like you could make antidepressants work a month faster. Best case scenario, you can make antidepressants work better. Maybe after a month, the cells have lost some confidence in the autoreceptors, but they’re still keeping serotonin somewhere below the natural amount based on the anomalous autoreceptor reading. So maybe blocking the autoreceptors would mean a faster, better, antidepressant.

Luckily we already knew a chemical that could block these – pindolol. Pindolol is a blood-pressure-lowering medication, but by coincidence it also makes it into the brain and blocks this particular autoreceptor involved in serotonin homeostasis. So a few people started giving pindolol along with antidepressants. What happened? According to some small unconvincing systematic reviews, it did seem to kind of help make antidepressants work faster, but according to some other small unconvincing meta-analyses it probably didn’t make them work any better. It just made antidepressants go from taking about four weeks to work, to taking one or two weeks to work. It also gave patients dizziness, drowsiness, weakness, and all the other things you would expect from giving a blood-pressure-lowering medication to people with normal blood pressure. So people decided it probably wasn’t worth it.


And then there’s buspirone.

Buspirone is generally considered a 5-HT1A agonist. The reality is a little more complicated; it’s a full agonist of presynaptic autoreceptors, and a partial agonist of postsynaptic autoreceptors(uh, imagine the customer in the other side of the teleconference also has an audiometer).

Buspirone has a weak anti-anxiety effect. It may also weakly increase sex drive, which is a nice contrast to SSRIs, which decrease (some would say “destroy”) sex drive. Flibanserin, a similar drug, is FDA-approved as a sex drive enhancer.

Buspirone stimulates presynaptic autoreceptors, which should cause cells to release less serotonin. Since high serotonin levels (eg with SSRIs) decreases sex drive, it makes sense that buspirone should increase sex drive. So far, so good.

But why is buspirone anxiolytic? I have just read a dozen papers purporting to address this question, and they might as well have been written in Chinese for all I was able to get from them. Some of them just say that decreasing serotonin levels decreases anxiety, which would probably come as a surprise to anyone on SSRIs, anyone who does tryptophan depletion studies, anyone who measures serotonin metabolites in the spinal fluid, etc. Obviously it must be more complicated than this. But how? I can’t find any explanation.

A few books and papers take a completely different tack and argue that buspirone just does the same thing SSRIs do – desensitize the presynaptic autoreceptors until the cells ignore them – and then has its antianxiety action through stimulating postsynaptic receptors. But if it’s doing the same thing as SSRIs, how come it has the opposite effect on sex drive? And how come there are some studies suggesting that it’s helpful to add buspirone onto SSRIs? Why isn’t that just doubling up on the same thing?

I am deeply grateful to SSC commenter Scchm for presenting an argument that this is all wrong, and buspirone acts on D4 receptors, both in its anxiolytic and pro-sexual effects. This would neatly resolve the issues above. But then how come nobody else mentions this? How come everyone else seems to think buspirone makes sense, and writes whole papers about it without using the sentence “what the hell all of this is crazy”?

And here’s one more mystery: after the pindolol studies, everyone just sort of started assuming buspirone would work the same way pindolol did. This doesn’t really make sense pharmacologically – pindolol is an antagonist at presynaptic 5-HT1A receptors; buspirone is an agonist of same. And it doesn’t actually work in real life – someone did a study, and the study found it didn’t work. Still, and I have no explanation for this, people got excited about this possibility. If buspirone could work like pindolol, then we would have a chemical that made antidepressants work faster, and treated anxiety, and reduced sexual dysfunction.

And here’s one more mystery – okay, you have unrealistically high expectations for buspirone, fine, give people buspirone along with their SSRI. Lots of psychiatrists do this, it’s not really my thing, but it’s not a bad idea. But instead, the people making this argument became obsessed with the idea of finding a single chemical that combined SSRI-like activity with buspirone-like activity. A dual serotonin-transporter-inhibitor and 5-HT1A partial agonist became a pharmacological holy grail.


After a lot of people in lab coats poured things from one test tube to another, Merck announced they had found such a chemical, which they called vilazodone (Viibryd®).

Vilazodone is an SSRI and 5-HT1A partial agonist. I can’t find how its exact partial agonist profile differs from buspirone, except that it’s more of a postsynaptic agonist, whereas buspirone is more of a postsynaptic antagonist. I don’t know if this makes a difference.

The FDA approved vilazodone to treat depression, so it “works” in that sense. But does its high-tech promise pan out? Is it really faster-acting, anxiety-busting, and less likely to cause sexual side effects?

On a chemical level, things look promising. This study finds that vilazodone elevates serotonin faster and higher than Prozac does in mice. And this is kind of grim, but toxicologists have noticed that vilazodone overdoses are much more likely to produce serotonin toxicity than Prozac overdoses, which fits what you would expect if vilazodone successfully breaks the negative feedback system that keeps serotonin in a normal range.

On a clinical level, maybe not. Proponents of vilazodone got excited about a study where vilazodone showed effects as early as week two. But “SSRIs take four weeks to work” is a rule of thumb, not a natural law. You always get a couple of people who get some effect early on, and if your study population is big enough, that’ll show up as a positive result. So you need to compare vilazodone to an SSRI directly. The only group I know who tried this, Matthews et al, found no difference – in fact, vilazodone was nonsignificantly slower (relevant figure). There’s no sign of vilazodone working any better either.

What about sexual side effects? Vilazodone does better than SSRIs in rats, but whatever. There’s supposedly a human study – from the same Matthews et al team as above – but sexual side effects were so rare in all groups that it’s hard to draw any conclusions. This is bizarre – they had a thousand patients, and only 15 reported decreased libido (and no more in the treatment groups than the placebo group). Maybe God just hates antidepressant studies and makes sure they never find anything, and this is just as true when you’re studying side effects as it is when you’re studying efficacy.

Clayton et al do their own study of vilazodone’s sexual side effects. They find that overall vilazodone improves sexual function over placebo, probably because they used a scale that was very sensitive to the kind of bad sexual function you get when you’re depressed, and not as sensitive to the kind you get on antidepressants. But they did measure how many people who didn’t start out with sexual dysfunction got it during the trial, and this number was 1% of the placebo group and 8% of the vilazodone group. How many people would have gotten dysfunction on an SSRI? We don’t know because they didn’t include an active comparator. Usually I expect about 30 – 50% of people to get sexual side effects on SSRIs, but that’s based on me asking them and not on whatever strict criteria they use for studies. Remember, the Matthews study was able to find only 1.5% of people getting sexual side effects! So we shouldn’t even try to estimate how this compares. All we can say is that vilazodone definitely doesn’t have no sexual side effects.

I can’t find any studies evaluating vilazodone vs. anything else for anxiety, but I also can’t find any patients saying vilazodone treated their anxiety especially well.

There’s really only one clear and undeniable difference between vilazodone and ordinary SSRIs, which is that vilazodone costs $290 a month, whereas other SSRIs cost somewhere in the single digits (Lexapro costs $7.31). If you’re paying for vilazodone, you can take comfort in knowing your money helped fund a pretty cool research program that had some interesting science behind it. But I’m not sure it actually panned out.


Encouraged by Merck’s success…

(not necessarily clinical success, success at getting people to pay $290 a month for an antidepressant)

…Takeda and Lundbeck announced their own antidepressant with 5-HT1A partial agonist action, vortioxetine. They originally gave it the trade name Brintellix®, but upon its US release people kept confusing it with the unrelated medication Brilinta®, so Takeda/Lundbeck agreed to change the name to Trintellix® for the American market.

Vortioxetine claimed to have an advantage over its competitor vilazodone, in that it also antagonized 5-HT3 receptors. 5-HT3 receptors are weird. They’re the only ion channel based serotonin receptors, and they’re not especially involved in mood or anxiety. They do only one thing, and they do it well: they make you really nauseous. If you’ve ever felt nauseous on an SSRI, 5-HT3 agonism is why. And if you’ve ever taken Zofran (ondansetron) for nausea, you’ve benefitted from its 5-HT3 antagonism. Most antidepressants potentially cause nausea; since vortioxetine also treats nausea, presumably you break even and are no more nauseous than you were before taking it. Also, there are complicated theoretical reasons to believe maybe 5-HT3 antagonism is kind of like 5-HT1A antagonism in that it speeds the antidepressant response.

After this Takeda and Lundbeck kind of just went crazy, claiming effects on more and more serotonin receptors. It’s a 5-HT7 antagonist! (what is 5-HT7? No psychiatrist had ever given a second’s thought to this receptor before vortioxetine came out, but apparently it…exists to make your cognition worse, so that blocking it makes your cognition better again?) It’s a 5-HT1B partial agonist! (what is 5-HT1B? Apparently a useful potential depression target, according to a half-Japanese, half-Scandinavian team, who report no conflict of interest even though vortioxetine is being sold by a consortium of a Japanese pharma company and a Scandinavian pharma company). It’s a 5-HT1D antagonist! (really? There are four different kinds of 5-HT1 receptor? Are you sure you’re not just making things up now?)

If we take all of this seriously, vortioxetine is an SSRI with faster mechanism of action, fewer sexual side effects, additional anti-anxiety effect, additional anti-nausea effect, plus it gives you better cognition (technically “relieves the cognitive symptoms of depression”). Is any of this at all true?

A meta-analysis of 12 studies finds vortioxetine has a statistically significant but pathetic effect size of 0.2 against depression, which is about average for antidepressants. In a few head-to-head comparisons with SNRIs (similar to SSRIs), vortioxetine treats depression about equally well. Patients are more likely to stop the SNRIs because of side effects than to stop the vortioxetine, but SNRIs probably have more side effects than SSRIs, so unclear if vortioxetine is better than those. Wagner et al are able to find a study comparing vortioxetine to the SSRI Paxil; they work about equally well.

What about the other claims? Weirdly, vortioxetine patients have more nausea and vomiting than venlafaxine patients, although it’s not significant. Other studies confirm nausea is a pretty serious vortioxetine side effect. I have no explanation for this. Antagonizing 5-HT3 receptors does one thing – treats nausea and vomiting! – and vortioxetine definitely does this. It must be hitting some other unknown receptor really hard, so hard that the 5-HT3 antagonism doesn’t counterbalance it. Either that, or it’s the thing where God hates antidepressants again.

What about sexual dysfunction? Jacobsen et al find that patients have slightly (but statistically significantly) less sexual dysfunction on vortioxetine than on escitalopram. But the study was done by Takeda, and the difference is so slight (a change of 8.8 points on a 60 point scale, vs. a change of 6.6 points) that it’s hard to take it very seriously.

What about cognition? I was sure this was fake, but it seems to have more evidence behind it than anything else. Carlat Report (paywalled) thinks it might be legit, based on a series of (Takeda-sponsored) studies of performance on the Digit Symbol Substitution Test. People on vortioxetine consistently did better on this test than people on placebo or duloxetine. And it wasn’t just that being not-depressed helps you try harder; they did some complicated statistics and found that vortioxetine’s test-score-improving effect was independent of its antidepressant effect (and seems to work at lower doses). What’s the catch? The improvement was pretty minimal, and only shows up on this one test – various other cognitive tests are unaffected. So it’s probably doing something measurable, but it’s not going to give you a leg up on the SAT. The FDA seriously considered approving it as indicated for helping cognition, but eventually decided against it on the grounds that if they approved it, people would think it was useful in real life, whereas all we know is that it’s useful on this one kind of hokey test. Still, that’s one hokey test more than vilazodone was ever able to show for itself.

In summary, vortioxetine probably treats depression about as well as any other antidepressant, but makes you slightly more nauseous, may (if you really trust pharma company studies) give you slightly fewer sexual side effects, and may improve your performance on the Digit Symbol Substitution Test. It also costs $375 a month (Lexapro still costs $7). If you want to pay $368 extra to be a little more nauseous and substitute digits for symbols a little faster, this is definitely the drug for you.


In conclusion, big pharma spent about ten years seeing if combining 5-HT1A partial agonism with SSRI antidepressants led to any benefits. In the end, it didn’t, unless you count benefits to big pharma’s bottom line.

I’m a little baffled, because pharma companies generally don’t waste money researching drugs unless they have very good theoretical reasons to think they’ll work. But I can’t make heads or tails of the theoretical case for 5-HT1A partial agonists for depression.

For one thing, there’s a pretty strong argument that buspirone exerts its effects via dopamine rather than serotonin – a case that it seems like nobody, including the pharma companies, is even slightly aware of. If this were true, the whole project would have been doomed from the beginning. What happened here?

For another, I still don’t get the supposed model for how buspirone even could exert its effects through 5-HT1A. Does it increase or decrease serotonergic transmission? Does it desensitize presynaptic autoreceptors the same way SSRIs do, or do something else? I can’t figure out a combination of answers to this question that are consistent with each other and with the known effects of these drugs. Is there one?

For another, the case seems to have been premised on the idea that buspirone (a presynaptic 5-HT1A agonist) would work the same as pindolol (a presynaptic 5-HT1A antagonist), even after studies showed that it didn’t. And then it combined that with an assumption that it was better to spend hundreds of millions of dollars discovering a drug that combined SSRI and buspirone-like effects, rather than just giving someone a pill of SSRI powder mixed with buspirone powder. Why?

I would be grateful if some friendly pharmacologist reading this were to comment with their take on these questions. This is supposed to be my area of expertise, and I have to admit I am stumped.

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95 Responses to The Vision Of Vilazodone And Vortioxetine

  1. Calion says:

    >(Why don’t the autoreceptors notice the original problem – that you have too little serotonin and are depressed – and work their magic there? Not sure. Maybe depression affects whatever sets the autoreceptors, and causes them to be set too low? Maybe the problem is with reception, not transmission? Maybe you have the right amount of serotonin, but you want excessive amounts of serotonin because that would fix a problem somewhere else? Maybe you should have paid extra for the premium model of presynaptic autoreceptor?)

    Maybe because depression has an important function, and just magically waving it away would be a terrible idea?

    • Scott Alexander says:

      But how would the autoreceptors know that?

      (more seriously, I think if you posit that there’s something involved in telling the autoreceptors that, then it reduces to the case where depression affects whatever sets the autoreceptors)

      • Calion says:

        You’ll have to bear with me because I know very little about psychiatry (as opposed to psychology).

        The autoreceptors know that because it’s literally a built-in feature. You don’t have too little serotonin. You have the amount you need right now given your current situation (well…some aspects of your current situation anyway). If you happen to ingest something that boosts your serotonin levels, you’ll likely just keep doing that instead of working out whatever is causing your depression. So the autoreceptors say, “nope, we’re moving back to your current overall hedonic level; no cheating.” (I realize your tongue was in your cheek, but you had some reason for asking.)

        But yeah, I think you’re right that, biochemically, the, or rather a, root of depression is going to be whatever sets those autoreceptors—presuming that what you’re saying about how depression functions in the brain is correct. I’m a bit of a skeptic on psychiatry—I put it about where I put econometrics, as mostly voodoo. This post of yours has not done much to change that opinion.

        • Vanzetti says:

          >You have the amount you need right now given your current situation

          And if your depression leads to suicide, did you need it, too?

          • Clutzy says:

            We don’t have suicide numbers for the stone age, but based on some other societies that we have decent numbers on, suicide is a negligible risk from the pre-20th century human POV. Physical labor decreases the risk of attempts. Farm life in the pre-industrial and even early industrial age was so dangerous that people preferred meat packing to it as a profession. The Amish have little suicide. People who exercise every day have little suicide.

          • Calion says:

            >And if your depression leads to suicide, did you need it, too?

            I would say that, in general, suicide is a result of trying to ignore what your depression is telling you.

          • kaelthas says:

            The Amish have little suicide. People who exercise every day have little suicide.

            I would assume that is because they have little depression.

          • Cliff says:

            I would assume that is because they have little depression.

            Are you unaware of the mood-stabilizing effects of exercise?

          • Radu Floricica says:

            No no no. The idea is that the feedback loop is much higher, and _not_ biochemical. After all, you can get depressed when you hear a single sentence, and can get cured when you hear another sentence (“dad died” and “I love you”, for quick examples).

            It’s a bit like predictive coding. What you see/hear/feel is probably 90% controlled by the system’s expectations about what you should see/hear/feel. Trying to solve the problem just from a biochemical point of view is pretty difficult when you’re only dealing with part of the model (and quite likely a minority part). So it being complicated and confusing and with very unexpected and variable results makes sense.

            So why are people still looking only at this part of the model? Probably because that’s where the light is.

      • sclmlw says:

        Do the autoreceptors have only the one function you specified above, or is it that they have only one known function? This reminds me of so many other cell signaling cascades that look simple at first but then turn out to be a tiny part of a web of interactions. You mentioned that vortioxetine had a bunch of effects on lesser-known 5-HT receptors. What about the SSRIs? Do we know anything about how they affect those receptors? What about signalling outside 5-HT pathways? Is there a kinase map we can look at for each of these agents to at least try and see if their signaling effects really are ‘similar’? It sounds like there’s a lot more hiding under the surface and we just haven’t looked under there in any kind of a systematic way. (Maybe we have, but this is not my area of expertise and you didn’t mention more than that one company was casting about for additional mechanistic interactions.)

        Just because we don’t yet know much about a signaling molecule doesn’t mean it’s unimportant. And given that we’re talking about a bunch of different drugs with potentially diverse cell-signaling dynamics I’d expect nothing less than that the effects are driven by a complex combination of signals through receptors we haven’t yet realized are important. We’re watching only one or two of those signals and wondering why we don’t understand what’s happening.

      • jimmy says:

        The term “saturation” seems to imply a nonlinear effect, but is that really the case? Or do SSRIs continue working for about a month after you quit too?

        If it’s the latter, it looks like an implementation of a low pass filter, and it’s not hard to see how that could be helpful. If your serotonin level determines how depressed you are and represents something like “how well your life is going”, then you probably wouldn’t want a good day to fool you into thinking that everything is great or a bad day to fool you into thinking that things are terrible. If you add a low pass filter, then by the time your autoreceptors allow your new normal to drift up, it’s likely that things have actually gotten better and that you can trust this trend to continue. In that case, the receptors would “know” simply by trusting the state estimates more than the measurement data on timescales shorter than about a month (does a month seem about right length of time to start trusting “my life is actually better now”?).

        Of course, that’s just a made up story without evidence, but it doesn’t seem particularly implausible either.

    • kaelthas says:

      That is highly unlikely. If you are depressed, you not only feel like shit, you also don’t get shit done, and you are less attractive as sexual partner, friend, teammate and employee. A bad depressive Episode can cost you your job, your partner and your friends, even if you don’t commit suicide. What advantage could possible make up for that?

      • jimmy says:

        You have to consider what the available alternative is.

        Panicking isn’t optimal, and can directly cost you your life. However, simply disregarding fear gets you killed too. “Feeling fear when appropriate and maintaining the composure needed to let it motivate extreme efforts without sacrificing wise choice of direction” isn’t something you can so easily encode in the level of a single chemical. Sensitivity to fear *is*, but then if there’s any real danger you’re just stuck between a choice of “freak out and respond ineffectively to danger” and “fail to notice the urgency, and respond ineffectively to danger”.

        It might be better to be less sensitive to fear on the margin if you’re prone to panic, but it’s still the case that the fear has a function. In other other times you might be better off with more fear. Or a level of fear that is high enough that you can’t deal with it well now, but that it’s continued presence would motivate you to become more courageous and therefore more capable in the next event. “Depression is actually a good thing in all cases, full stop” is clearly too strong a take, but so is “lol, this feels bad, and bad is bad so I don’t wanna”.

  2. Ttar says:

    I’m now remembering that Scott reviewed PiHKAL, a book about a Chemical Love Story which he compared to My Immortal, and regarding which he spent an entire section discussing Freud and Jung.

    Huh. I wonder what would happen if I added the number of days since the My Immortal article, subtracted all the Sabbaths, multiplied by the number of completion…

  3. GeneralDisarray says:

    What I tell my clients is, no study has every found that depressed people have lower serotonin levels and the damn things don’t work immediately anyway, so the antidepressant effect is necessarily related to whatever attempt your brain is making to return to homeostasis. I think I always suspected it had something to do with monoamine oxidase, and that the primary affect relates to relative stimulation of the other monoamines. Functionally, SSRIs seem to dampen arousal-mediated positive feedback loops, maybe related to a prioritization function? (If depression serves a function it seems to me to be about underlying imperatives that circumstances require you to discard, like an “erase” function in the subjective universe of priorities, which is why major life changes/narcissistic injury is so strongly associated with suicide.)

    Thanks for this, btw. I always find these analyses informative.

    • Scott Alexander says:

      I think some studies have found depressed people have lower serotonin levels, see eg this study which discusses impaired serotonin transmission in the brains of suicide victims. I don’t know how seriously to take them, though.

      I don’t understand the MAO theory. If you increase serotonin, the homeostatic compensation is to try to decrease serotonin by increasing MAO, which ought to decrease dopamine and norepinephrine, which sounds like it would be bad.

      I strongly agree about dampening arousal-mediated positive feedback loops (this is a very out-of-date version of my thoughts on the subject), but I’ve never found any particularly enlightening research about this – can you suggest any?

      • GeneralDisarray says:

        Increased Mao means that dopamine and norepinephrine are now out of balance (low), with ramped up production (fewer autoreceptors or whatever) to compensate over time, relative to serotonin (more autoreceptors), which is why the whole process takes weeks or months (receptor changes) rather than immediately (direct stimulation).

        My Neuroscience knowledge base is a bit out of date (was an interest, went in a more clinical direction), and tended more towards the intersection of functionality and neurophysiology, but I’ll see if I can remember anything (decompiling proceduralized conclusions has gotten more cumbersome with age). I’ll get back to you.

      • GeneralDisarray says:

        It’s not that I don’t think serotonin is involved in depression, more that it’s unlikely to be the primary factor. I liked your rambling essay on feedback loops. In my undergraduate days I wrote a review of evidence of the link between recurrent otitis media in childhood and OCD diagnosis as an adult, and I got pretty excited when PANDAS became a thing (I’ve been saying since then that the biggest new breakthroughs in psychiatry are going to come from research on neuroinflammatory and autoimmune processes, which might just be starting to happen.)

        The problem with OCD/tic disorders is that, in order to inhibit (countermand) something you have to activate it into your conscious attention first. When the inhibition part of that process is hobbled, the subroutine takes off (messaging problem). High dose SSRIs can dampen the effect, but they don’t address the core problem, which is failure of negative feedback loop associated with attention. (I treated for a couple years someone with really severe post-encephalitic Tourettes, and that person taught me an awful lot about the subjective nature of this process.) The most severe form of this is Lesch-Nyhan (if you haven’t read it, there’s a great New Yorker article here:, also another related phenomenon here:

        • anonymousskimmer says:

          Hmm, thanks. I have a tic-related OCD. Also had a minor bout of gout in my late teens or early 20s. I used to bite my fingernails, and when running out of fingernails to bite started on the cuticle/nail-fold and knuckle skin.

        • Gerry Quinn says:

          So the Revolutionary in Gene Wolfe’s _Shadow of the Torturer_ was not science fiction after all…

    • Lodore says:

      No one would dispute that there’s a cognitive element to depression. But that doesn’t mean there isn’t a serotonin connection––and note that the amount of serotonin is secondary to the uptake of serotonin.

      Good evidence that serotonin affects mood is found in the experience profile of MDMA use: i.e. an initial hedonic, socially-oriented high followed a day or two later by a low that has the same phenomenology as a depressive episode. Though the experimental programme still needs work, there remains good prima facie case for pursuing MDMA as an antidepressant.

      My point being that MDMA is first to last a release agent for serotonin at the presynaptic level. My personal hunch about depression (it’s a feedback loop where an initial perception of low status – which may be behavioural or physiological in origin – causes self-reinforcing low-status behaviours via damped serotonin system action) matches the action of MDMA. That is, increased uptake of serotonin causes perceptions of higher social status, which causes euphoria; post-drug, the perception of losing status as uptake falls off brings on a minor depressive episode.

      • GeneralDisarray says:

        Sure it’s involved, but I doubt very much it’s the primary factor (SSRIs dampen the process of they’re working, but nobody who’s ever taken one would tell you they fix any problem, other than maybe premature ejaculation). The interpetsonal process you’re describing is I imagine related, but too narrow. It reminds me of physiological psychologists years ago trying to use birdsongs as a model for OCD (arguably related, too narrow).

        I think MDMAs promise as an adjunct to psychotherapy for PTSD (time-limited) is much more promising than using it as an antidepressant. Those damn homeostatic processes would, I imagine, fuck it up in much the same way that Benzodiazapines fuck up chronic anxiety.

      • dualmindblade says:

        MDMA is more than just a serotonin releaser, for one thing it also releases dopamine, very few drugs have comparable effects.

  4. broblawsky says:

    One of psychiatry’s many embarrassments is how many of our drugs get discovered by accident

    AFAICT, deliberate drug discovery is pretty hard. In vitro testing seems to be overwhelmingly likely to produce compounds that do not have significant in vivo impacts, especially compared to existing drugs. When was the last time a genuinely new psychiatric drug was discovered?

    • Lodore says:

      I’m not disagreeing with you, but maybe it’s worth qualifying with the observation that drug discovery is hard, given the constraints of the psychiatric model. Which is to say, it’s hard to find drugs that have no hedonic value, do not interfere (too much) with day-to-day functioning, and which are safe in clinically active doses.

      As Scott observed in the main post, Shulgin and collaborators practically had a production line going that generated new psychoactive drugs, even if it was mostly from two families (phenethylamines and tryptamines). Now, while “safe at clinically active doses” is non-negotiable, the other two constraints are more open to interpretation. And I wonder if that’s what we need to relax if we are to gain traction on psychiatric illness.

    • block_of_nihilism says:

      Definitely. It’s interesting to note that some of our most promising recent discoveries in the field of anti-depressive agents come from individual experimentation with illegal drugs (ketamine, psychedelics, MDMA for PTSD). Instead of working with a theoretical approach to drug design, working from our experimental knowledge of receptor function, we should be focusing on any agent we find that is used/abused by people suffering from mental illness? That way, at least we know the agent has SOME effect at the level of emotion/behavior before spending time and money on further development.

  5. Steve Sailer says:

    One of the world’s most useful non-psychiatric drugs is ivermectin, which treats a host of nasty ailments including the horrible tropical disease of river blindness.

    I could be wrong, but my impression is that ivermectin was discovered in the 1970s almost purely experimentally, without any theoretical clue ahead of time as to why it might work.

    Are brain drugs harder to discover in that kind of Edisonian fashion because you can’t easily reproduce the workings of a brain in vitro, but it’s risky to treat living human brains? But, on the other hand, it’s even harder to get a good theory of which kind of molecule would be effective in a brain because our theory of how brains work is even worse than our theory of bodies work?

    • Garrett says:

      Medications for other more “objective” diseases are a lot easier to test and screen in animal models. This is especially true for antibiotics or (in this case) anti-parasitics. Give your lab mice parasites. Give them the test drug. See if they still have parasites.

      Conditions like depression (also Alzheimer’s disease) are really, really challenging because we don’t have a reliable model of what an underlying or intermediate cause is. So we don’t know how to find mice with the same problem. At-best, we can find mouse conditions which sort-of look like they are the same thing to people. But determining if your mouse is actually human-condition depressed as opposed to in chronic pain, sedated, or any other host of possible conditions isn’t really possible yet.

  6. Gon says:

    Lundbeck is a Danish company so you’ll have to find another reason to incriminate the Swedish researchers. Enjoyed the post though!

  7. dpm96c says:

    (Just logging into my account to say that I love the pharmaceutical posts—probably my favorite genre on the site.)

  8. At a considerable tangent …

    You mention drugs that increase or decrease the sex drive. One category of pharmaceutical that humans have been searching for for the past few thousand years is aphrodisiacs. Are you saying that we now have some?

    My favorite line on the subject is someone’s comments that, considering how many foods were believed to be aphrodisiac in the Middle Ages, it looks as though all anyone really needed was a square meal.

    • Scott Alexander says:

      Flibanserin, bupropion, and buspirone are all weak and inconsistent aphrodisiacs.

      I did have one patient who, even though bupropion otherwise worked well for him, had to stop it because his sex drive got so high his girlfriend couldn’t keep up. But that’s pretty atypical.

      • Clutzy says:

        So it was a typical heterosexual relationship?

        haha I am the funniest.

      • Garrett says:

        Also consider clavulanic acid (uncertain whether amoxicillin is also required, though it alone is insufficient).

      • Sylvie says:

        Cabergoline, MDMA + tadalafil, and higher doses of androgens seem to be pretty strong and consistent.

      • unreliabletags says:

        This anecdote is mindblowing.

        Isn’t coping with unrealistic desire, like, the fundamental task of adulthood? I’ve always put it in the same bucket as working for a living or planning my next meal. Do people actually expect their sex drives to be satisfied? Or treat it as an actionable problem when they’re not?

        I also experienced a sharp and uncomfortable rise in libido on bupropion. Fortunately it calmed down after a few days, but I don’t think it would have occurred to me to stop taking it for that reason.

        • eric23 says:

          Yes, selfish people.

        • Doesntliketocomment says:

          But it was an actionable problem. One that the patient sorted out by discontinuing the medication.

          Also I think you are either underestimating the patient’s enhanced sex drive, which might have been on the level of satyriasis, or overestimating how much he was aware of his heightened libido. I didn’t read this as “My wife won’t satisfy my needs!” but more as a “my wife says I’m really annoying her with my overactive sex drive, I don’t see it but I will take her at her word.” If you don’t have an accurate picture of the behavior it becomes very difficult to regulate.

      • SpaltedMaple says:

        People have been searching for anaphrodisiacs, drugs that decrease the sex drive, for at least a thousand years or so. Do you know of any that work in more than fifty percent or so of people? Barring things like chemical castration or similar – those sorts of things, while sometimes efficacious, have some pretty nasty side effects. Maybe you know of some compound that didn’t make it to market because of sky-high sexual dysfunction rates?

    • KarenEliot says:

      We already have PT-141, which gives you the libido of a 14 year old, literally. It has 3 disadvantages:
      – if you take too much and are not used to it, you get nauseous. At least the libido boost lasts much longer than the nausea.
      – at the moment it‘s one of these underground peptides you get at bodybuilding websites
      – and that is because the company which holds the patent tried to get it approved as a nasal spray, and the spray raised the users‘s blood pressure by a few points.

      It‘s related to Melanotan-2, which was developed as chemical tanning agent, which is why bodybuilder adopted it first. Melanotan-2 also raises libido and is guaranteed to turn you into a horny and slightly orange tinted Doc Bronze, minus degree and muscles.

      • Cliff says:

        What form is it sold in through bodybuilding websites? Nasal spray?

        The prescription drug is an injector and the drug has a half-life of a couple of hours so it’s not exactly long-lasting. Also if used too much it causes hyperpigmentation which can be permanent.

        Have you used it?

        • KarenEliot says:

          It’s sold in vials for injection, but you can probably put it in a spray as well.
          I tried Melanotan-II, but mostly remember that I turned orange and that the libido boost was so long (noticeable for days) and so strong that I found it rather scary. So I would expect PT to be less orange and more libido, but you can search reddit for people talking about their experiences with that stuff.
          I don‘t quite get why someone would want a libido boost that lasts longer than a few hours. The stuff literally makes you think with your dick, which is not a good thing at all.

  9. estelendur says:

    The fact that vortioxetine is “supposed” to stop nausea I find so frustrating as to be almost offensive. I had to stop taking it because it turns out that sharp stomach pain and intense nausea is a great way to condition myself to not want to take my medication.

  10. Ian Maxwell says:

    For what my own single datum is worth, I offer it here: I was taking sertraline for depression but switched to vilazodone specifically because of anorgasmia. This side effect was completely eliminated when I switched, and I have never had any sexual dysfunction issues at all since switching. (I did discover some other interesting side effects, but that’s a whole different story.)

    • Lodore says:

      I did discover some other interesting side effects, but that’s a whole different story.

      Come on man, spill! You can’t flash your ankle and just leave us like this!

      • Ian Maxwell says:

        Well, maybe not that interesting. The main one has been nightmares, which were never a problem for me before. Strictly speaking this only happens if I missed a dose or took it much later than usual or something, so whether this is “a side effect of taking the medication” is arguable, but it happens pretty much 100% of the time in that case, and they are so vivid and intense that I can barely sleep and I’m exhausted in the morning. I realize you aren’t supposed to discontinue antidepressants suddenly so I should expect some bad effects from doing so, but I never had anything like this happen with sertraline.

        (Side note: often the content of these dreams isn’t “bad” in any way I can really point to—nothing terrible actually happens, I’m not being physically hurt or watching my children be hurt or anything like that—and they are identifiable as “bad dreams” only because they are so distressing. I found this kind of curious actually.)

        • dionisos says:

          Definitely interesting and strange.

        • PFafBg5iQ says:

          Really interesting. I think you should report this to your doctor and make sure he reports it at your country’s drug agency. Anecdotes like this could provide insights and theories in decades 🙂

        • Lodore says:

          I’m not being physically hurt or watching my children be hurt or anything like that—and they are identifiable as “bad dreams” only because they are so distressing.

          There’s a reasonably well-attested link between serotonin expression and self-perceptions of social status. The relationship is not straightforward (and varies by species) but it’s either a real thing or part of a real thing.

          So I wonder if these dreams are content-free bad because they place you in a low-status world, due to the drop-off in serotonin uptake. And the reason they manifest as dreams is that the drop-off is sharp rather than gradual on account of missing the dose.

          I guess the answer is to capture the mood of the dream as best you can next time it happens, and interrogate it for a social dimension.

  11. alistair says:

    I’m a little baffled, because pharma companies generally don’t waste money researching drugs unless they have very good theoretical reasons to think they’ll work.

    Wouldn’t they only care whether or not it sells? Maybe they thought it wouldn’t matter if it didn’t work better than SSRIs because as long as it got approved enough people would buy it (in the hope that because it’s different it might work for them).

    • Peter Gerdes says:

      But the approval process is reasonably related to demonstrated efficacy and it’s a lot harder to convince doctors to script a drug without evidence it’s effective. Unless there was just no other idea to pursue why not put the money in a good candidate?

  12. Peter says:

    SSRIs take a month to work? My experience with SSRIs is that the effects start kicking in a few days before I start taking them. The placebo effects are marvellous and having a bit of active there too really helps me to believe in it. I think there are a couple of other things too. Firstly there’s the “distress made manifest” thing, the way a hard-to-sum-up state of mind can be translate into a nice concrete SSRI dose, perhaps it makes things easier to process. There’s the legitimisation thing, the “someone else thinks my distress is clinically significant” aspect, access to conversations about pills with fellow sufferers (including being able to gripe about side effects), the ability to say, “I’m doing something about this, look, I’ve made an appointment to see the doctor to get back on the pills/increase my dose”. I suspect a lot of this wouldn’t work so well if it was just a sugar pill and everyone knew it.

    • Doesntliketocomment says:

      I feel this 100%. Every time there is a switch in medication there is that hopeful feeling of doing something to improve myself and the idea that maybe this one will be what I really needed. Unfortunately that feeling always seems to outshine the actual effects when they finally kick in.

  13. pyentropy says:

    I think antipsychotics are worth mentioning. Seroquel is the only monotherapy approved for bipolar depression by FDA [1]. It’s a partial agonist for 5HT-1A but it’s a antagonist for 5HT-2A and 5HT-2C which both happen to be receptors that suicide victims have a lot [2][3]. And then we have an opposite theory that 5HT-2A promotes active coping [4]. And then we have Seroquel being an antagonist on autoreceptors only which makes them receptor agonists.

    The entry barrier for creating and testing drugs is way too high. In some future rationalist society:
    * MAOIs should be prescribed more
    * all drug precursors should be freely available, and synth should be liberalized
    * severely depressed patients should be allowed to easily sign up for all kinds of drug trials
    * GABA & opioid upregulation drugs should be researched
    * Voltage-sensitive sodium channels & their effect on glutamate should be researched (Lamotrigine), VDCC should be researched (Lyrica)

    My opinion is that if Scott or some SSC commenters became FDA benevolent dictators for a year, with just a few decisions a dramatic positive impact on society could be made. E[liberalized drug design killing people] < E[legal drugs like alcohol killing people].

    • Sylvie says:

      5-HT2A doesn’t promote active coping by itself, psychedelics have a completely different effect on 5-HT2A than normal serotonin.

    • Peter Gerdes says:

      I heartily agree with this. Just looking at the beneficial effect Shulgin has had on psychiatric meds when he was just trying to trip balls should be more than convincing enough.

      Frankly, I think the underlying problem is that it’s almost impossible to stop systematic abuse of any mechanism that allows for drug experimentation by people looking to make money selling miracle cures. I agree we need to free up experimentation but it’s hard to work out what would be an effective way to regulate this in the US (we love hard rules and have overlapping law enforcement which makes creating the kind of informal – go ahead and experiment and it’s fine if that involves your sophisticated PhD having friends but no commercial use or things that amount to the practice of medicine).

      Don’t get me wrong I think even if we fuck it up more liberalization would be a huge net benefit. But unfortunately people are just too afraid of making a change and someone getting hurt even if it’s a net win.

  14. Manx says:

    Anecdotal info on Vilazadone from my psychiatric practice:
    1) I never start with Vilazadone for what it’s worth – always with something cheaper – usually lexapro, prozac, or zoloft.

    2) I have switched several people from one SSRI to vilazadone specifically for sexual side effect complaints. Sorry I don’t have hard numbers – maybe about 10.

    3) For about half of these people, vilazodone was a large improvement in terms of sexual side effects. I can think of 3 cases where people were very happy with the switch, and basically claimed it worked fully for their depression/anxiety but without the sexual side effects. I don’t have a control group that I switched from one SSRI to a random other SSRI to compare this to though.

    4) For about half – it was difficult to tell if there was improvement in sexual side effect. People said things you would expect them to say if they wanted it to work but were unsure – like ‘I think it might be a little better’.

    5) I have also tried vilazadone for treatment resistant depression because it’s supposedly stronger. Again guessing numbers, around 6 times? I have 0 success cases with this. Basically if you’ve already tried 2 other SSRIs, vilazadone doesn’t seem to have any sort of magical extra properties that put it over the edge.

    6) Vilazadone seems to have several other side effects, which have sometimes been intolerable. The greatest of these is horrible night sweats. I’ve had enough people complain about this (half?) that I warn people about it now before trialing it. Also seems to cause more insomnia, jitteriness, racing heart than lexapro/prozac/zoloft.

    So, my conclusion is that it is worth *trying* vilazadone as a substitute for other SSRIs if there is a complaint of sexual side effects, but I still think it is overall a worse medication given it’s greater other side-effect profile and price point. Would not start with it. Also, none of this is controlled in anyway and is completely subject to every bias I have, including recall bias, and small sample size.

    I haven’t prescribed much trintellix – probably due to having less colleagues who recommend it. You only have so many spots for switching people to novel SSRIs.

  15. Nancy Lebovitz says:

    I believe we need to know a lot more about how healthy bodies work before we can get good at designer drugs.

  16. enkiv2 says:

    > except that it’s more of a postsynaptic agonist, whereas buspirone is more of a postsynaptic antagonist


  17. block_of_nihilism says:

    Another issue to consider are the complex (and basically unknown) interactions between different receptors and their downstream pathways. For example, Scott covered the recent study in human patients showing the anti-depressive effects of ketamine infusion were dependent upon the opioid receptor contradicted a general belief that NMDA antagonism was responsible for this activity (
    However, a recent report (Based in rodents, but still interesting) found that both NMDA antagonism AND mu-opioid receptor activation were required for these effects ( So, a more reasonable hypothesis explaining ketamine’s anti-depressive and anti-suicidal activity is something like (NDMA blockade * mu-receptor agonism= effect). It’s worth noting that these interactions might be occurring on any scale from an intracellular level, all the way up to interactions between distinct functional brain regions.

    Similarly, think about the “dirty” nature of some of our most effective psych drugs (lithium comes to mind). It’s their combined effect on multiple receptors at the same time that makes them effective. If someone teases out one receptor target of this dirty drug, then generates an agent that specifically targets that receptor, it is unlikely that the new specific agent will match the efficacy of the original, “dirty” drug.

    If we look at it this way, it is not surprising that this type of linear-thinking research fails to generate effective therapies, especially in something as complicated as the brain.

    • Peter Gerdes says:

      Except the research scientists end up with a library of very targeted antagonists and agonists and you’d think they’d then be able to work out effects that are dependent on combinatorial activation.

      • block_of_nihilism says:

        That’s true! I think the barriers to true understanding are still pretty significant, as with each added compound, the number of possible combinations increases. Also, it is never certain if your particular compound ONLY binds one receptor or if its effects are due to a direct action on a particular receptor vs some other indirect manner of activity.

  18. Sylvie says:

    here are some more or less relevant studies:

    5-HT2B receptors are required for serotonin-selective antidepressant actions

    in rats,
    1. 2B receptors are required for the chronic effects of SSRIs to work, both cellularly and behaviorally
    2. agonizing 2B receptors causes — acutely — the same effect as SSRIs

    Neural basis of major depressive disorder: Beyond monoamine hypothesis. this does lean somewhat on adult human neurogenesis, but that seems to be still up in the air, and it still works with just neuroplasticity.
    key quote: Interestingly, although common antidepressants work as inhibitors of monoamine transporters, the BDNF–mTOR pathway and the astrocytes–FGF2 pathway may be monoamine-independent. This suggests the possibility that antidepressants may have unknown target proteins other than monoamine transporters in their action mechanisms.

    there’s a nice diagram.

    Enhancing AMPA to NMDA throughput as a convergent mechanism for antidepressant action also has a pretty good overview of the pathways involved, though the claim about imipramine and fluoxetine acting on glutaminergic receptor phosphorylation is a bit shaky.

    in case the studies above don’t mention it, tianeptine, the serotonin reuptake *enhancer*, works just as well (if not, ime, better than) as SSRIs.

    i’ll try to return to this and present something more coherent and maybe look for an actual answer to your questions, but the wishy-washy answer for now is just that the face value agonism/antagonism is not necessarily very high up on what ‘actually’ causes a drug’s effects (though i think we knew already)

  19. Tarpitz says:

    My totally undeducated crank theory is that while “depression” is in some sense a natural category, it’s not one that’s likely to be conducive to any one widely effective treatment, because I think we’re essentially grouping superficially/partially similar sets of symptoms with different causes and mechanisms, rather as if we were trying to come up with a medicine for chest pain that treated TB, CoViD-19, lung cancer, cracked ribs and the common cold. If that’s right, it’s no wonder treatment trials are an absolute nightmare.

    • pyentropy says:

      There are many cancer types and there’s no general treatment but we know that we need to fix abnormal cell growth. But when it comes to depression, all we know is that it happens in the brain (and millions of otherwise healthy people become sick due to some stressful event!). What do we need to fix? There’s no doubt that there’s no fix-it-all single receptor or neurotransmitter but we need better classification & clusters of mechanisms/causes.

      Unlike permanently losing a leg, depression is not losing a brain. The neural network (the major source of complexity) is functional — you are conscious, you can speak, move, and make decisions. I don’t see a reason why we can’t effectively treat it.

  20. Doug S. says:

    As an engineer, “saturated” would mean to me that the autoreceptor system is working as hard as it can and is being overwhelmed, the same way that if you have a weak air conditioning system your house can still get too hot during a heat wave even if you’ve set the thermostat lower. It’s like you’re already shouting at the top of your voice and the audiometer is still telling you that you’re too quiet – it might be true but there’s nothing you can do about it!

  21. nupi says:

    I can feel SSRI coming on very clearly and generally quickly.
    Escitalopram pretty much from the first dose (also, annoying side effects like dizziness and mild nausea) and also disappearing right about when the half life suggest it would disappear.
    Fluoxetine after a few days, then it remained fairly steady (not surprising given its loooong half life)
    Venlafaxine took about two weeks but then came with a sudden massive shift (that was serious ‘I will kill myself or failing that, let me just sleep and booze’ type MDD), too.
    FWIW, I also could tell immediate (and delayed, surprisingly) release bupropion coming and going…
    Duloxetine I do not remember much about other than it gave me weird obsessions.

    So yes, some people are just sensitive. The strongly serotonergic ones also give me very vivid dreams, FWIW.

    • Peter Gerdes says:

      Of course you can feel the drug effects immediately. It’s the anti-depressive effect which takes a month. Things like sexual side effects seem to happen instantly. If I take enough fluoxetine I stop being able to have an orgasm that day.

      • nupi says:

        The above was referring to anti depressant effects which never took anywhere near a month for me (Bupropion kicks in in lesd than an hour for immediate release pills and within hours for the XR). I agree that side effects come on almost immediately.

        I do have an extraordinarily fast metabolism though (sometimes I feel like I am eating all day and still only gain weight with intense focus on it).

  22. Cameron Mahoney says:

    This is only somewhat related, but I was flabbergasted when Cold Springs Harbor Lab knocked out the gene/protein that were targets of various cancer drugs in some cell lines and found that it didn’t appear to affect the cancer drug’s efficacy at all compared to cell lines with the supposed target.

    An article about the paper from Nature:

    It really does feel like we’re frequently flying blind, and that for a lot of so-so / marginally effective drugs, we’re probably getting something quite wrong.

    I wonder if anyone has done and/or if it is possible to do the same type of experiment for anti-depressants in those little brain-simulacrum-organoids that there are frequently consciousness questions and vaguely horrifying ethical questions about?

  23. Atlas says:

    One of psychiatry’s many embarrassments is how many of our drugs get discovered by accident. They come from random plants or shiny rocks or stuff Alexander Shulgin invented to get high.

    But every so often, somebody tries to do things the proper way. Go over decades of research into what makes psychiatric drugs work and how they could work better. Figure out the hypothetical properties of the ideal psych drug. Figure out a molecule that matches those properties. Synthesize it and see what happens. This was the vision of vortioxetine and vilazodone, two antidepressants from the early 2010s. They were approved by the FDA, sent to market, and prescribed to millions of people. Now it’s been enough time to look back and give them a fair evaluation. And…

    …and it’s been a good reminder of why we don’t usually do this….

    In conclusion, big pharma spent about ten years seeing if combining 5-HT1A partial agonism with SSRI antidepressants led to any benefits. In the end, it didn’t, unless you count benefits to big pharma’s bottom line.

    This reminds me of an interesting general question I unfortunately don’t have anything particularly insightful to say about: To what extent is progress in technology driven by serendipitous tinkering vs. abstract theory? This post moves my priors slightly in the former direction. Nassim Nicholas Taleb is very fond of this sort of thing:

    Inadvertent Discoveries

    The discovery of human epistemic arrogance, as we saw in the previous chapter, was allegedly inadvertent. But so were many other discoveries as well. Many more than we think. The classical model of discovery is as follows: you search for what you know (say, a new way to reach India) and find something you didn’t know was there (America). If you think that the inventions we see around us came from someone sitting in a cubicle and concocting them according to a timetable, think again: almost everything of the moment is the product of serendipity. The term serendipity was coined in a letter by the writer Hugh Walpole, who derived it from a fairy tale, “The Three Princes of Serendip.” These princes “were always making discoveries by accident or sagacity, of things which they were not in quest of.” In other words, you find something you are not looking for and it changes the world, while wondering after its discovery why it “took so long” to arrive at something so obvious. No journalist was present when the wheel was invented, but I am ready to bet that people did not just embark on the project of inventing the wheel (that main engine of growth) and then complete it according to a timetable. Likewise with most inventions.

    Sir Francis Bacon commented that the most important advances are the least predictable ones, those “lying out of the path of the imagination.” Bacon was not the last intellectual to point this out. The idea keeps popping up, yet then rapidly dying out. Almost half a century ago, the bestselling novelist Arthur Koestler wrote an entire book about it, aptly called The Sleepwalkers. It describes discoverers as sleepwalkers stumbling upon results and not realizing what they have in their hands. We think that the import of Copernicus’s discoveries concerning planetary motions was obvious to him and to others in his day; he had been dead seventy-five years before the authorities started getting offended. Likewise we think that Galileo was a victim in the name of science; in fact, the church didn’t take him too seriously. It seems, rather, that Galileo caused the uproar himself by ruffling a few feathers. At the end of the year in which Darwin and Wallace presented their papers on evolution by natural selection that changed the way we view the world, the president of the Linnean society, where the papers were presented, announced that the society saw “no striking discovery,” nothing in particular that could revolutionize science.

    We forget about unpredictability when it is our turn to predict. This is why people can read this chapter and similar accounts, agree entirely with them, yet fail to heed their arguments when thinking about the future. Take this dramatic example of a serendipitous discovery. Alexander Fleming was cleaning up his laboratory when he found that penicillium mold had contaminated one of his old experiments. He thus happened upon the antibacterial properties of penicillin, the reason many of us are alive today (including, as I said in Chapter 8, myself, for typhoid fever is often fatal when untreated). True, Fleming was looking for “something,” but the actual discovery was simply serendipitous. Furthermore, while in hindsight the discovery appears momentous, it took a very long time for health officials to realize the importance of what they had on their hands. Even Fleming lost faith in the idea before it was subsequently revived.

    In 1965 two radio astronomists at Bell Labs in New Jersey who were mounting a large antenna were bothered by a background noise, a hiss, like the static that you hear when you have bad reception. The noise could not be eradicated—even after they cleaned the bird excrement out of the dish, since they were convinced that bird poop was behind the noise. It took a while for them to figure out that what they were hearing was the trace of the birth of the universe, the cosmic background microwave radiation. This discovery revived the big bang theory, a languishing idea that was posited by earlier researchers. I found the following comments on Bell Labs’ website commenting on how this “discovery” was one of the century’s greatest advances:

    Dan Stanzione, then Bell Labs president and Lucent’s chief operating officer when Penzias [one of the radio astronomers involved in the discovery] retired, said Penzias “embodies the creativity and technical excellence that are the hallmarks of Bell Labs.” He called him a Renaissance figure who “extended our fragile understanding of creation, and advanced the frontiers of science in many important areas.”

    Renaissance shmenaissance. The two fellows were looking for bird poop! Not only were they not looking for anything remotely like the evidence of the big bang but, as usual in these cases, they did not immediately see the importance of their find. Sadly, the physicist Ralph Alpher, the person who initially conceived of the idea, in a paper coauthored with heavyweights George Gamow and Hans Bethe, was surprised to read about the discovery in The New York Times. In fact, in the languishing papers positing the birth of the universe, scientists were doubtful whether such radiation could ever be measured. As happens so often in discovery, those looking for evidence did not find it; those not looking for it found it and were hailed as discoverers.

    We have a paradox. Not only have forecasters generally failed dismally to foresee the drastic changes brought about by unpredictable discoveries, but incremental change has turned out to be generally slower than forecasters expected. When a new technology emerges, we either grossly underestimate or severely overestimate its importance. Thomas Watson, the founder of IBM, once predicted that there would be no need for more than just a handful of computers.

    That the reader of this book is probably reading these lines not on a screen but in the pages of that anachronistic device, the book, would seem quite an aberration to certain pundits of the “digital revolution.” That you are reading them in archaic, messy, and inconsistent English, French, or Swahili, instead of in Esperanto, defies the predictions of half a century ago that the world would soon be communicating in a logical, unambiguous, and Platonically designed lingua franca. Likewise, we are not spending long weekends in space stations as was universally predicted three decades ago. In an example of corporate arrogance, after the first moon landing the now-defunct airline Pan Am took advance bookings for round-trips between earth and the moon. Nice prediction, except that the company failed to foresee that it would be out of business not long after.

    (Of course, I, personally, just read those lines on a screen, so…)

    • Nancy Lebovitz says:

      What might be extraordinary is the ability to notice anomalies and take advantage of them. Fleming noticed his spoiled petri dishes. Who cares about light and dark bands from a slit? Or some rock which fogs photographic film? There’s probably a lot of important clues we’re missing.

      This doesn’t mean everyone gets handed equally good anomalies.

    • Peter Gerdes says:

      I don’t know where I would put Shulgin on that scale. Sure, he doesn’t seem to reason about receptor affinities but as far as systematic exploration of how changes in various chemical properties affect psychedelic experiences he probably has the most systematic approach we’ve got. I mean he has all sorts of views on how substituting bromine for whatever tends to affect the properties of the compound.

      I’d describe more what he does as early systematic investigations into an area before a truly effective theoretical framework has been developed.

  24. Peter Gerdes says:

    I’m really beginning to think that the strategy of just finding another chemist who wants to get high might be a *much* more efficient route.

    Think about it. You get a feedback loop with real (even if just a few people…him and his friends) human reports within days or weeks and he explores out a large space of chemicals with decent information about potential toxicity in humans far before a large well-funded pharma company would even get to primate tests. Sure, he won’t give you info on long term anti-depressive effect but you can do that later. Like what if you just had a Shulgin for feeling happy or anxiety free instead of tripping balls?

    So what if we just paid a bunch of chemists who want to be the next Shulgin to do it in nice we’ll-funded labs. I’m sure someone can figure out a way around the ethics rules since it’s not like people aren’t doing this kind of crap anyway now we just get them to write up results and not just repeat the same stuff other people are using. Hell it seems like we manage to get studies that involve people self-administering their illicit narcotic of choice so surely we can manage this somehow.

    • Garrett says:

      > just finding another chemist who wants to get high

      Not really. There’s a huge industry (predominantly in China) based on cranking out yet-another-molecule which gets you high but currently isn’t technically illegal in the US. They’re based on derivatives of fentanyl, canabanoids, etc. It’s to the point that the toxicologists I’ve talked to are annoyed because by the time they managed to develop an effective *test* for them, the manufacturers have switched to something else. They’d much rather have people taking good old-fashioned heroin/cocaine/whatever where at least they can trivially test for it and have established treatments for overdoses.

    • nupi says:

      Mainly because getting high is bad, mkay (TM).

      Stuff that gets you high often lands on schedule lists making it harder or impossible to prescribe (some weird exceptions exist, benzos spring to mind in particular).

      It also tends to build tolerance fairly quickly often meaning it will stop working (or at least not work as well) or build dependence (see benzos again and basically any opioid).

  25. Scchm says:

    Let me try for an explanation Scott is asking for in “I still don’t get the supposed model for how a drug even could exert its effects through 5-HT1A.”

    1A serotonin receptor is a negative feedback receptor. When a molecule of serotonin attaches itself to a 1A receptor on the cell, the receptor is stimulated and the negative feedback is turned on: the release of serotonin from the cell goes down.

    A molecule of 1A antagonist or partial agonist competes against serotonin at 1A receptor. If an antagonist is attached to the receptor, the receptor is not stimulated at all. If a partial agonist is attached to the receptor, the receptor is stimulated to a lesser degree than with serotonin.
    When a partial agonist of 1A receptor such as vilazodone competes against serotonin and attaches itself to 1A receptor, it stimulates the receptor less than serotonin. The negative feedback from the receptor is lesser, the release of serotonin from the cell does not go down as much.

    So, to respond to Scott’s question as to how SSRI + serotonin 1A partial agonist is theoretically supposed to be more effective than simple SSRI. In animal models, SSRI increases the serotonin concentration between serotonergic neurons by about 50% because the feedback mechanism through 1A receptor shuts down serotonin release pretty fast. Vilazodone (SSRI + serotonin 1A partial agonist) increases the serotonin concentration by about 150%. [numbers from memory]

    Accordingly, the pharma hypothesized that vilazodone is going to be more effective than a simple SSRI. Indeed, vilazodone does increase serotonin more that SSRI in humans as evidenced by much higher rates of nausea for vilazodone. (Nausea is a generic serotonin effect). But, as Scott correctly notes, this does not translate into higher efficacy. The problem is that serotonergic hypothesis of depression is wrong.

    • Scott Alexander says:

      I understand that for vilazodone. Why did they think buspirone, which AFAIK is a full agonist, would do it? Or am I misunderstanding, and their billing vilazodone as “SSRI plus buspirone” was a marketing gimmick that didn’t make sense?

      • Scchm says:

        Buspirone is a partial agonist of 5HT1A receptors with efficacy of about 60%. In that respect buspirone may appear to be similar to vilazodone, which is also a partial agonist. In the same way as vilazodone, buspirone, it seems, should also enhance serotonin concentration. But it does not happen in reality. Billing vilazodone as “SSRI plus buspirone” makes no sense because buspirone and its metabolites (mostly 6-OH buspirone) are not sufficiently potent to occupy 5HT1A receptors in real-world clinical situations.

        Quoting from : “Low levels of 5-HT1A receptor occupancy by buspirone at clinically
        effective doses have been reported previously in human positron
        emission tomography studies (Rabiner et al., 2000; Passchier et al.,
        2001). A single dose of 10 or 40 mg of buspirone occupies ~5%
        5-HT1A receptors in healthy human subjects (Rabiner et al., 2000;
        Passchier et al., 2001).”

  26. Scchm says:

    Another question from Scott: “Why spend hundreds of millions of dollars discovering a drug that combined SSRI and buspirone-like effects, rather than just giving someone a pill of SSRI powder mixed with buspirone powder?”

    Answer: Because 1A partial agonist competes for the receptor with serotonin. Serotonin binds to 1A receptor extremely tightly.

    Buspirone binds to 1A receptor approximately 10 times less tightly than serotonin. As a result buspirone occupancy of 1A receptors (the proportion of receptors bound with buspirone) is negligible. Buspirone has practically no action on 1A receptors.

    In contrast, vilazodone binds to 1A receptor several times more tightly than serotonin. Vilazodone occupancy of 1A receptors is significant. The pharma expected that vilazodone is going to work unlike simply giving buspirone with SSRI. But it did not happen (see Scott’s post).

  27. Scchm says:

    Scott writes (tong-in-cheek): “really? There are four different kinds of 5-HT1 receptor? Are you sure you’re not just making things up now?”

    Ha-ha. There are actually five different kinds of 5-HT1 receptor: 1A, 1B, 1D, 1E and 1F.

  28. JRG says:

    To make the picture more confusing, Sunovion recently published data from clinical trials for SEP-363856, a 5HT1A antagonist that also antagonizes trace amine receptors (specifically TAAR-1). It appears to be reasonably effective compared to other drugs in its class. The thing is, it was tested as an antipsychotic in hospitalized people with schizophrenia. The compound was developed semi-intentionally, basically a high volume behavioral screen for agents that had a D2 receptor antagonist profile in nice but that chemically had astronomically low affinity for D2 receptors. Probably one or both of those pathways indirectly modulates dopamine pathways but things get handwavy very quickly. They really play up the 5HT1 antagonism as a big deal.

    When I read this, my first thought was “if this works, why is buspirone not a fantastic neuroleptic?” Or course then I go to look and mirabile dictu, there is a smallish literature on buspirone as adjunct and monotherapy for psychosis.

    Just in case 5HT1 wasn’t confusing enough…

    • Scchm says:

      Incorrect. SEP-363856 is a partial agonist of 5-HT1A and full agonist of TAAR1. The potency of SEP-363856 at 5-HT1A (Ki about 300 nM) is insufficient to compete with serotonin at the receptor, so its anti-psychotic action is probably due to TAAR1 agonism.

  29. Nav says:

    Jumping on the REBUS horse again to try and explain everything here (emphasis mine).

    The self or ego is an important (perhaps central) high-level prior that DMN dynamics may instantiate (Carhart-Harris and Friston, 2010). The DMN is a particularly influential system, sitting atop a (uniquely) deep functional hierarchy in humans (Friston, 2018). We reason that high-level systems and the beliefs they encode have an informationally efficient, compressing influence on more elemental information held and processed below them. The high-level systems therefore function to route or canalize thought and behavior, sometimes in an overly constraining way that restricts self-awareness and obstructs new learning. If the gravitational pull of beliefs or behaviors becomes excessive, this can leave an agent feeling estranged from deeper aspects of his or her self, as well as from other people—and from a sense of purpose and meaning in life.

    To summarize, the REBUS/anarchic brain model is derived from a synthesis of the entropic brain hypothesis and free-energy principle, and particularly the latter’s close links with hierarchical predictive coding. It recognizes that psychedelics induce an acute state of heightened brain entropy via their action on the serotonin system (Carhart-Harris, 2018a), then looks to prediction coding and hypothesizes that increased brain entropy reflects a relaxation of the precision weighting of priors (REBUS) that coincides with liberation of bottom-up signaling (anarchic brain).

    Basically: serotonin doesn’t “make you feel better” so much as it “makes your mind/priors more flexible”. The process of learning and adjustment as a result of increased flexibility is what takes a month (I’m sure everyone’s heard/experienced the phenomenon where psychedelic experiences only show an impact on belief/behavior after several weeks).

    And there’s no reason why “more serotonin = more happiness”, because the improvement in mood is fundamentally mediated by your environment and how it feeds back into your cognitive processes. Often, people take SSRIs once they’re in stable life situations very different than the situations in which their past priors developed. In this case, the SSRI can “cure” the depression. But if their environment does not meet their psychic needs even with their relaxed priors, the depression will persist or even intensify.

    My point is that curing depression not only a neurological problem, it’s a combination neurological and ecosystematic problem. And I recognize that I’m going against scientific orthodoxy (and this community’s general beliefs) by even making this post, but I figured it’s worth a shot anyway.

    • pyentropy says:

      Every psychiatrist wants their patient to be in a state where they can analyze & improve their responses to events as well as improve their environment/relationships such that they feel better. And that’s fine. The problem is that not only SSRIs fail some patients but they don’t even help some patients to be in a less depressed state where they can fix the environment & event response problems.

      Also, how does nerve growth, priors, entropy explain bipolar patients that want to kill themselves one they and think they are God himself the other day? There are over 70M people living this way.

      • Nav says:

        The problem is that not only SSRIs fail some patients but they don’t even help some patients to be in a less depressed state where they can fix the environment & event response problems.

        I agree, but the OP is about “some antidepressants that affect serotonin appear to be approximately as effective as other antidepressants that also affect serotonin in related ways. How mysterious!” (and not: “these don’t work at all”, to which I wouldn’t have replied). My post was intended to suggest a unified causal mechanism and to suggest that a purely neurological approach might inherently miss some aspects of the problem.

        Also, how does nerve growth, priors, entropy explain bipolar patients that want to kill themselves one they and think they are God himself the other day? There are over 70M people living this way.

        I assume we’re discussing depression and anxiety (i.e. diagnoses treated with SSRIs) and not bipolar disorder, which has different causes and mechanisms and requires different treatment. So, I don’t see how it’s relevant.

        • pyentropy says:

          I’m not claiming that unipolar and bipolar depressions are equivalent, but the fact that we can replicate all the chronic depressive symptoms with a short acute bipolar episode to me suggests that the underlying mechanism (of feeling bad) is not some long term neurotrophic factor or priors flexibility but some neurotransmitter(s) balance issue.

          As I’ve said in other comments, my optistimic view is that most depressions (typical or atypical) don’t involve permanent damage or long term nerve growth issues, but rather a chemical imbalance that we could completely fix in the future – although therapy will be still required for preventing relapses and learning how to be in a control of a situation. I’d even go further and say that the number of mechanisms of action that will cover most of the cases will be less than a dozen. And that “most cases” will be 95% of patients (otherwise healthy people that didn’t have something like a stroke). I just looked it up: 10x ECT has a partial remission rate of 75-80% measured by HAM-D-24.

          • Nav says:

            the fact that we can replicate all the chronic depressive symptoms with a short acute bipolar episode to me suggests that the underlying mechanism (of feeling bad) is not some long term neurotrophic factor or priors flexibility but some neurotransmitter(s) balance issue

            I strongly disagree, on the grounds of a “third variable effect”. In particular, humans have a(t least one) dynamic layer mediating between neurotransmitters, behavior, and environment/perception. I say “dynamic” because it exists as a part of complex feedback systems, meaning the “mediating layers” can influence neurotransmitter production and vice versa.

            In that sense, both the depressive aspects of bipolar disorder and depression proper may have parallel manifestations in terms of raw neurochemistry, but this says little about their causation, unless we believe that neurochemistry is a closed system with respect to the outside world and also fully determines behavior.

            permanent damage or long term nerve growth issues

            I think we’re talking about different things regardless. The article I linked has quite little to do with these things. It’s instead about patterns of neuron activity, which act as the mediating factor(s) I mentioned above.

            These patterns are physiological in the sense that they exist as processes operating on our “neurological substrate” (and thus they are influenced by changes in neurotransmitter levels), but they are not fully determined by neurochemistry, nor do they have a strong connection to “nerve growth” or “damage”. I also believe these patterns represent the true causal mechanism behind many of the items in the DSM, which is a claim that psychoanalysis made over a century ago but that only recently has an empirical backing in the physical sciences.

  30. Spiritkas says:

    Another inbuilt assumption which often goes unquestioned is the agonist and antagonist dichotomy. The reality must be more nuanced and there is a huge category of different functionality that must be occurring. If you put in a molecule and it somehow disables one of the several 5HT receptors…how is it disabled? Is it a total knockout or partial, what aspect of functionality is changed. The idea of lock and key with protein structures being equal to physical functionality is limited and more of a metaphor than not as there are the chemical affinities, concentration thresholds, and other factors whereby proteins are not little biological nano machines with either enough or not enough of them present and functional or broken.

    Either way if you break that receptor or even temporarily disable it…does it then do anything else? Perhaps it does 3 things and you stop it from doing 1, but then it does the other 2 things at different rates or does them strangely. Perhaps the regular signal says to stack the next block you find to the left of the last block, but this drug confused your receptor into stacking to the right vs the standard ‘disabled narrative’ of no stacking occurring. That could explain why one way of breaking the receptor causes nausea and the other decrease nausea, yet they are both ‘meant’ to be breaking the same receptor.

    You have so many feedback loops, some into unknown mechanisms that it could be turtles all the way down, or at least additional layers of complexity. If you start stacking blocks on the wrong side or start putting them on top or whatnot, then how does that affect all the other interconnected metabolic processes that were expecting left stacked blocks or no blocks?

    It can get even stranger where a mechanism is meant to stack left if it gets a weak signal and stacking right with a strong signal. One drug might stop all stacking affecting both output directions and all their flow on effects. A different drug that ‘does the same thing’ might stop only the left side weak signal stacking while the right side stacking continues or vice versa. Then you could have the stacking signals reversed with strong signal left stacking and weak on the right, which could have a myriad of effects not simply a reverse effect. Or even just super confused / disordered stacking which is not an ‘everything cancels out’ equivalent to no stacking, the erratic stacking patterns could confuse the hell out of other connected processes.

    The very simple explanation of it works harder or it stops working with agonist vs antagonist might be just as much the culprit as the number of receptors, feedback loops, and dependant relationships between them. Why would we be so lucky that one part of these complex metabolic pathways gives us a wonderful binary impact?

    A final thought I had was about how similar these chemicals and proteins can be. If you break a communication pathway for a 5HTa receptor with its stack left instructions, it is possible it then mimics another receptor‘s signal in the regular or in a strange way. The differences often involve small changes with additions or subtractions of a few functional groups. So perhaps one drug stops 5HTa activity and that’s it while another drug causes strange new signals to be sent to 5HTb via a partially broken intermediary. It wouldn’t have to be perfect, perhaps a weak extra anti anxiety effect comes from a certain percentage of broken molecules becoming mimicking molecules to become an agonist or antagonist to a related or even not very related pathway? This uneven and varied degradation of functionality effects on our target pathway using different drugs may extend much further than the agonist vs antagonist framework.