Chronic Psychitis

Some people have asked my opinion on a recent spate of articles like Is Depression Partly Caused By An Allergic Reaction? and Depression May Be Caused By Inflammation.

Standard disclaimer: I’m not a researcher in this field, I’m not board-certified as a full psychiatrist yet, and what I remember of biochemistry is limited to being pretty sure there’s something called a “Krebs cycle” involved somewhere. That having been said:

This is pretty legit.

Start with From inflammation to sickness and depression, Dantzer et al (2008), who note that being sick makes you feel lousy [citation needed]. Drawing upon evolutionary psychology, they theorize this is an adaptive response to make sick people stay in bed (or cave, or wherever) so the body can focus all of its energy on healing. A lot of sickness behavior – being tired, not wanting to do anything, not eating, not wanting to hang around other people – seems kind of like mini-depression.

All of this stuff is regulated by chemicals called cytokines, which are released by immune cells that have noticed an injury or infection or something. They are often compared to a body-wide “red alert” sending the message “sickness detected, everyone to battle stations”. This response is closely linked to the idea of “inflammation”, the classic example of which is the locally infected area that has turned red and puffy. Most inflammatory cytokines handle the immune response directly, but a few of them – especially interleukin-1B and tumor necrosis factor alpha – cause this depression-like sickness behavior. It is noted that:

In general, animals injected with IL-1ß or TNF-a stay in a corner of their home cage in a hunched posture and show little or no interest in their physical and social environment unless they are stimulated. Specifically, they show decreased motor activity, social withdrawal, reduced food and water intake, increased slow-wave sleep and altered cognition

Here are some other suspicious facts about depression and inflammation:

– Exercise, good diet and sleep reduce inflammation; they also help depression.

– Stress increases inflammation and is a known trigger for depression.

– Rates of depression are increasing over time, with the condition seemingly very rare in pre-modern non-Westernized societies. This is commonly attributed to the atomization and hectic pace of modern life. But levels of inflammation are also increasing over time, probably because we have a terrible diet that disrupts the gut microbiota that are supposed to be symbioting with the immune system. Could this be another one of the things we think are social that turn out to be biological?

– SSRI antidepressants, like most medications, have about five zillion effects. One of the effects is to reduce the level of inflammatory cytokines in the body. Is it possible that this is why they work, and all of this stuff about serotonin receptors in the brain is a gigantic red herring?

– It’s always been a very curious piece of trivia that treating depression comorbid with heart disease significantly decreases your chances of dying from the heart disease. People just sort of nod their heads and say “You know, mind-body connection”. But inflammation is known to be implicated in cardiovascular disease. If treating depression is a form of lowering inflammation, this would make perfect sense.

– Rates of depression are much higher in sick people. Cancer patients are especially famous for this. No one gets too surprised here, because having cancer is hella depressing. But it’s always been interesting (to me at least) that as far as we can tell, antidepressants treat cancer-induced depression just as well as any other type. Are antidepressants just that good? Or is the link between cancer being sad and cancer causing depression only part of the story, with the other part being that the body’s immune response to cancer causes inflammatory cytokine release, which antidepressants can help manage?

– Along with cancer, depression is common in many other less immediately emotion-provoking illnesses like rheumatoid arthritis and diabetes. The common thread among these illnesses is inflammation.

– Inflammation changes the activity level of the enzyme indoleamine 2,3 dioxygenase. This enzyme produces kynurenines which interact with the NMDA receptor, a neurotransmitter receptor implicated in depression and various other psychiatric diseases (in case your first question upon learning about this pathway is the same as mine: yes, kynurenines got their name because they were first found in dog urine).

– Sometimes doctors treat diseases like hepatitis by injecting artificial cytokines to make the immune system realize the threat and ramp up into action. Cytokine administration treatments very commonly cause depression as a side effect. This depression can be treated with standard antidepressants.

– Also, it turns out we can just check and people with depression have more cytokines.

There’s also some evidence against the theory. People with depression have more cytokines, but it’s one of those wishy-washy “Well, if you get a large enough sample size, you’ll see a trend” style relationships, rather than “this one weird trick lets you infallibly produce depression”.

But for me the strongest evidence against is a general feeling that it’s very easy to get lots of convincing evidence for a theory in medicine whether or not it’s true.

Twenty years ago, everyone was super-convinced that depression was caused by low serotonin levels. We found that depressed people on average had lower serotonin levels than non-depressed people. We found that giving people drugs that increased serotonin treated depression. We did lots of studies proving serotonin was a vital chemical that regulated mood. We found that genes affecting serotonin-related proteins were linked to depression. We did PET scans that found abnormally high levels of activity in serotonin-related enzymes in the brains of depressed people. It was all very convincing. And right now everyone’s pretty sure it’s wrong.

Ten years ago, everyone was super-convinced that depression was caused by under-secretion of the neuro-hormone BDNF and subsequent decline in hippocampal neurogenesis. It was dutifully found that depressed people had less BDNF than everyone else, and less hippocampal neurogenesis. Exercise, sleep, good diet, and all the other things that help depression were found to also raise levels of BDNF. Chemical pathways were trotted out by which effective antidepressants would probably raise BDNF levels. I think this theory is still very popular, but for the inflammation theory to be right someone will either have to disprove this one or tie it together with some theory of why inflammation decreases BDNF or low BDNF increases inflammation or something else. I do see some evidence that this is true, but to fully integrate the theories is going to take a lot more than that.

And these are just the two most recent and most famous. We have Freud’s psychoanalytic theory of depression, lots of people studying dysregulation of the hypothalamopituitaryadrenocortical axis, some pointers to dysregulation in the second messenger system, et cetera. All of these theories have great evidence.

Point is, now we have another theory that neatly explains how depression starts, how antidepressants work, why diet and exercise are good for you, and all the things all the other theories explained. Maybe the third time’s the charm?

A lot of the things in the body are really complex. Inflammation definitely affects serotonin – the indoleamine 2,3 dioxygenase enzyme acts on serotonin’s immediate precursor. It affects BDNF levels, as above, which in turn affect hippocampal neurogenesis. The hypothalamopituitaryadrenocortical axis releases cortisol, which downregulates the immune system and decreases the action of inflammatory cytokines. All of the anxiety-inducing life events and intrapsychic conflicts and secret desires to marry your mother that Freud thought caused depression produce a lot of stress, which both releases cortisol and reduces normal ability to regulate inflammatory response.

So basically all of these systems are intimately interconnected, and probably before this is done with researchers will find five more systems intimately interconnected with all of these. It might be that inflammation is the master system which causes a cascade of events in all of the others. It might be that one of the others is the master system. It might be that depression is a collection of multiple different diseases, and some are caused by one thing and others by another. It might be that looking for a “master system” is silly and that the true mathematical relationship between all of these things is such a chaotic process that all you can say is that they all stumbled together into the wrong attractor point and things deteriorated from there.

Anyway, all this is for much smarter people than me to figure out. The question I’m most interested in: can we treat depression by giving people anti-inflammatory drugs?

The answer seems to be: it depends how strongly you object to getting a heart attack.

Aspirin is a great anti-inflammatory drug. It’s pretty safe in adults (except for a small risk of GI bleeding) and it decreases risk of cardiovascular disease and cancer as well. If you could treat depression with aspirin, you’d be home free. However, the most convincing review I have seen for aspirin is unimpressed. It points out that some trials have shown negative effects for aspirin, and that long-term use of aspirin can increase intestinal permeability which decreases ability to regulation inflammation which is the opposite of what we want. Right now there isn’t much evidence on this issue, but what there is isn’t promising.

Most researchers have chosen to focus on celecoxib (Celebrex™®©, a high-tech next-generation anti-inflammatory). Here the evidence is actually very strong. Last month’s JAMA Psychiatry contained Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials, Kohler et al, (2014), which analyzes ten studies with a total of 4000 people taking celecoxib and finds an effect size similar to that of SSRI antidepressants. This is promising and exciting.

They add: “We found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks.”

That’s probably because they didn’t wait long enough. Celecoxib is very closely related to the infamous rofecoxib (Vioxx™®©) which got pulled from the market for quadrupling heart attack risk. Celecoxib is safer; it only increases your risk by some smaller amount depending on dose. Studies conflict, but maybe 33% for a standard regimen?

On the other hand, if ten percent of Americans are on SSRIs right now, and there are 1.5 million heart attacks per year in the US, and celecoxib increases that by 33%, then switching everyone from SSRI to celecoxib would cause…quick Fermi calculation…ignore interactions…50,000 extra heart attacks per year. Ouch.

Celecoxib is a good drug for its indicated uses, which involve treating chronic pain conditions that nothing else can treat safely. But it’s hardly something I’d want to start giving to every depressed patient who walks into a psychiatrist’s office. Maybe as a third line or fourth line drug for desperate people. But then, we already have plenty of good third-line and fourth-line drugs for desperate people. You want strong psychiatric medication and aren’t too concerned about the state of your cardiovascular system? Here, have an antipsychotic!

So in conclusion, I think the inflammatory hypothesis of depression is very likely part of the picture. Whether it’s the main part of the picture or just somewhere in the background remains to be seen, but for now it looks encouraging. Anti-inflammatory drugs do seem to treat depression, which is a point in the theory’s favor, but right now the only one that has strong evidence behind it has side effects that make it undesirable for most people. There’s a lot of room to hope that in the future researchers will learn more about exactly how this cytokine thing works and be able to design antidepressant drugs that target the appropriate cytokines directly. Until then, your best bets are the anti-inflammatory mainstays: good diet, good sleep, plenty of exercise, low stress levels, and all the other things we already know work.

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150 Responses to Chronic Psychitis

  1. Bugmaster says:

    > Aspirin is a great anti-inflammatory drug. It’s very safe (except for a smallish risk of GI bleeding)

    I have overdosed on aspirin once, and it caused GI bleeding. I would very strongly recommend against this experience, as it produced the highest amount of sustained pain that I have ever experienced in my life until that event. Granted, I have lived a pretty sheltered life, but still: GI bleeding is no fun.

  2. Douglas Knight says:

    Inflammation is not a concrete thing like serotonin, but an abstraction. So it’s a lot easier to fool yourself into thinking that depression is related to inflammation than to fool yourself into thinking that depression is related to serotonin. There are a lot more “inflammation-related proteins” than “serotonin-related proteins.” In part because it’s so easy to publish papers saying that the protein is “inflammation-related.”

    For the first half of this post, you don’t really use the abstraction: you could replace almost all of the uses of “inflammation” with “cytokines.” But at some point you do use it, because the point of an abstraction is to be used, to make connections between different concrete instantiations. But I think it is a bad abstraction and I advise against using it. At least, I strongly recommend structuring arguments as you did this post, with the use delayed as long as possible, so that if you eventually abandon the abstraction, as much as possible can be salvaged.

    • Sarah says:

      I was just about to say this. “Inflammation” in this context sounds like it means “increased levels of immunomodulatory chemicals that are associated with the immune response to infection.” Maybekindasorta. It certainly doesn’t mean “rubor, calor, dolor, tumor” because depressives aren’t walking around all red and swollen. It doesn’t mean “cytokines” because some cytokines are Th2-ish and some are Th1-ish and some are neither, and Th2 and Th1 inhibit each other (and most of the things associated with the diseases of modern life are Th2-ish rather than Th1-ish but NOT ALL.)

      I’ve spent a long three years up to my waist in these “systemic inflammation makes you sick in all the ways” papers, and I really hate to say “the body is complicated”, but without better data or better paper-reading technology, I’m pretty stuck with “the body is complicated.”

      Chronic inflammation (as measured by the most Obviously Bad immune markers like CRP) is associated with all the diseases of aging and modernity (cancer, heart disease, diabetes, Alzheimer’s, stroke). It’s also associated with stress, anxiety, and depression, as well as generally “being in bad shape” (obesity and lack of exercise.) I’m pretty confident of this, and I don’t think these correlations are all spurious.

      Where do I go from there, given that I don’t yet understand the primary “knobs” in the immune system because it has so many moving parts?

      *I still dream of doing a “systems biology” kind of research approach where we treat different immunomodulatory chemicals as a big damn directed graph and look at its spectral properties. i.e. find out what parts of the immune system we can shove and get a desired physiological response.

      *treat people who have actual real live illnesses with the treatments known to work for those illnesses, rather than guessing you can treat the “inflammation” directly. Epistemological humility.

      (I shudder at the thought of someone thinking “oh, you have a disease associated with inflammation! let’s try prednisone!”)

      *experiment with things that are known or believed to reduce inflammation and are just sort of good for you generally.

      Exercise, good diet, and sleep. Relaxation (and practices like yoga, meditation, or CBT that generally lower distress.) Low-carb or gluten-free diets seem suggestively good at clearing up autoimmune or inflammation-related problems. Probiotics seems to be “mildly good for you” for all sorts of things, and common sense says eating fermented food is a Good Thing.

      Things like curcumin which are anti-inflammatory [inhibits the TLR-4 and NF-κB signaling cascades] and have a (reasonably evidence-based) reputation as “adaptogens” (shit that makes you feel better in general).

      I mentioned curcumin off the top of my head, in particular because it’s a *food*, the active ingredient in turmeric, and a food traditionally known to be *good for you*, in India. Traditional use isn’t a reliable indicator of anything (remember the Doctrine of Signatures?) but it gives you reason to privilege a hypothesis, and also tells you something about safety (a popular seasoning is probably not too deadly, at least at the doses you find in your dinner.)

      • Douglas Knight says:

        The spectra of graphs are not subject to various biases, but I fear that the raw data has already been corrupted by confirmation bias.

      • Jaskologist says:

        Meditation is not necessarily beneficial, particularly if you’re already starting out in a questionable state of mind. Putting unusual things into your mind can be as unwise as putting unusual substances into your body.

        • Sarah says:

          I suspect (and this is from introspection alone) that how dangerous meditation is depends on how “heavy” you do it.

          Where “heavy” means “how much of your ordinary thought process do you shut down?” Very heavy meditation means focusing on one thing *completely*, shutting off your phonological loop, shutting off things like “feelings” and breaking down sense perceptions into their components. When I’ve done “heavy” meditation, it has done peculiar fragmenting things to my sensory experience of the world, and it felt potentially risky and I quit.

          Lighter meditation preserves complex thoughts like “feelings”, “intentions” or “words”. If you’re meditating on compassion, or meditating to the sound of soothing music, or allowing your mind to gently wander, that has a sort of “lighter” quality. These days I meditate regularly but it’s definitely the “fluffy-bunny” variety; it’s noticeably improved my mood and willpower and body awareness without causing any sensory abnormalities.

          • Jaskologist says:

            I would be very interested in a Rationalist guide to meditation, from a practical howto perspective. I’ve read a little on the subject, but never really been clear on what precisely it is I’m actually supposed to be doing.

            Plus, I’m not at all a spiritual person. My brain just seems to lack that module.

          • Firstly, there have been a few guides to meditation on LessWrong, such as here and here.

            Secondly, I’m not sure what materials you were reading, but I don’t think practical howto advice on meditation is that hard to find. The standard recommendation is Mindfulness in Plain English. I read it a few years ago, but from what I remember while it’s from an unquestionably Buddhist perspective it doesn’t invoke any mystical or supernatural concepts. If I’m remembering incorrectly though, I’m sure you could find materialist guides to meditation elsewhere, given how widely endorsed it is by mainstream psychology at this point.

            Thirdly, I have personally found that too many instructions and information make meditation harder, not easier, as it’s just more stuff to think and worry about while meditating. All you really need to know is

            – keep your attention on your breath
            – whenever your attention drifts from your breath, put it back
            – the goal is to clear your mind, but that being said if you’re trying too hard not to think it can be counter-productive. at some point the thoughts will naturally stop

            (That being said, I’m personally not that good at meditation, so take this advice with several grains of salt.)

          • Jaskologist says:

            Ok, then maybe I was doing it right after all. It’s just that I got absolutely nothing out of the experience. But, as mentioned elsewhere, my spiritual senses are very nearly blind.

          • Anonymous says:

            If you are looking for meditation instruction Google leigh Brasington for concentration (jhana) meditation

            Bad website design but pretty good clearly written intrusions. I think this is pretty safe. You can get pretty serious without ill effects. I think insight style meditation is where thjngs can get weird.

        • Illuminati Initiate says:

          Hmm, interesting…

          Does anyone else find the things “spirituality”/meditation/new age types talk about kind of… disturbing? Things like “breaking down the ego” and removing the “illusion” of the self? I certainly don’t want anything like that to happen to me. I am myself. Why would you want to eliminate yourself?

          Buddhism is terrifying itself, for the same reasons but more so. Like, Abrahamic religions are evil too, but they are evil in a way that’s more… familiar. “You must obey our insane rules or you will be tortured for eternity” is a familiar sort of evil, its an anthropomorphic cosmic horror story. It’s not that different from an all powerful version of various states and cultures that have existed throughout history, really. And I would say that they are probably worse overall. But Buddhism is disturbing. Like “people who willingly are absorbed by a hive mind” kind of disturbing.

          (I am not very familiar with Buddhist doctrine, but I think I’ve heard enough about it that this is not just some kind of misunderstanding. If I’ve made some kind of obvious misunderstanding someone can correct me.)

          • Anonymous says:

            >Things like “breaking down the ego” and removing the “illusion” of the self? I certainly don’t want anything like that to happen to me. I am myself. Why would you want to eliminate yourself?

            Do you go to sleep at night worried a different person will wake up?

          • Jaskologist says:

            Hinduism is very literally looking forward to being absorbed by a hive mind. Buddhism is closer to suicide, in my view. The goal is to escape suffering by escaping existence.

          • I agree that some aspects of Buddhism are disturbing. (I wrote some thoughts on the subject here.)

            That being said, I think there are at least three ways “breaking down the ego” can be interpreted which seem to have positive implications

            – Not having a running mental model of your own status, therefore eliminating the need for validation and maintenance of self-esteem.

            – Not having the illusion that one part of your brain under conscious control is opposed to another part of your brain out of conscious control – in reality, there’s no clear boundary

            – Not seeing a meaningful difference between your mind and the minds of other people, thus turning you into a more altruistic person and also letting you share in other people’s joy. (Not sure how this attitude can be achieved from a rationalist perspective, but other people manage to do it.)

            The issue is confusing, however, and I don’t really understand it myself. Buddhists and other religious types talk about losing the illusion of the self like it’s a euphoric and transcendental experience. Schizophrenics whom as one of their symptoms lose a sense of self talk about it like it’s a horrible, terrifying experience. People who experience ego death on psychedelics talk about it like it’s both terrifying and transcendental. So I’m not sure what’s really going on here.

            Also, it seems like half of the spiritual movements out there talk about eliminating the sense of self, while the other half talk about “finding your true self”. Some even manage to talk about both. I kind of feel like these are different names for the same thing somehow…?

          • Sarah says:

            I like having a self, I like acting in my self-interest and I like having self-esteem. I just figure that meditation is worth trying for its well-reported benefits, I don’t have to do it to the “highest level”, and I can quit if it seems to be taking me to a place I don’t like.

          • William O. B'Livion says:

            FYI, the Marines were (and maybe still are) teaching Mindfulness meditative practices (picture a bunch of really fit young men sitting crosslegged with loaded rifles about 6 inches in front of their knees.) and it *seemed* to reduce PTSD, helped them stay focused better during firefights and post-IED events etc.


            Having been one, the Marines are *not* into breaking down the ego.

            I have tried to practice it, and I’ve got a few things that once my mind gets on will just loop around forever. I find that starting to focus on my breathing and going into some of the “other stuff” in MM helpful in breaking those loops.

            Anonymous asks:

            Do you go to sleep at night worried a different person will wake up?

            No, I hope I do.

          • Illuminati Initiate says:


            Its not that I think meditation is suicide. It’s just that the way its advocates talk about the self as an obstacle to be overcome is kind of creepy.

          • I feel its fairly important to get into the details of a claim before rejecting it on a creepy/absurd heuristic. From my reading in psychology/social science I feel the extension of the self to one’s status is something that’s particularly harmful, firstly to the person’s hapiness, and secondly to others through the actions deriving from a feeling of the self being always under threat. Not really so confident about the other “selves” (haven’t really looked at them), but I defintely feel they’re roughly in line with what scientific evidence there is on the status one.

          • Kev says:

            >>”I am not very familiar with Buddhist doctrine, but I think I’ve heard enough about it that this is not just some kind of misunderstanding”

            HAHAHA Dunning-Kruger alert! You haven’t made a misunderstanding if you don’t know the slightest bit about what you’re talking about!

            Like most naive westerners, you see words that you are familiar with (ego, no-self, illusion etc) and interpret them cluelessly, in the scientific/materialistic sense, without actually researching what they meant metaphysically.

          • Illuminati Initiate says:

            If those words mean different things then its hardly my fault everyone has been translating them wrong.

            But yes, knowledge I have of eastern religion is… limited. Which is why I admitted this and said people are free to correct any misconceptions I have.

        • Daisy says:

          My mind and body used to completely freak out when I meditated, and I’d feel terrible afterwards. This was consistently true for years. I tried to make myself push through it a few times, but that was a bad idea.

          I had extremely good results doing a Mindfulness Based Self Compassion course (for info see as a starting point.) I can actually meditate on a regular basis now, by adopting a compassionate stance towards my experience.

          (And of course the emotional self-soothing and containment it teaches is useful everywhere, all the time, not just in in meditation. Would recommend to basically anyone. )

        • I think you need to be pretty hardcore to get to the point where you’re at risk of experiencing the Dark Night of the Soul. I don’t think patients encouraged by their therapists to try meditating for fitfteen minutes a day until they get over their depression are at much risk.

          I’ve heard the analogy that a beginner to meditation worrying about the dark night is like a beginner to weightlifting worrying about accidentally over-doing it and becoming all gross and veiny like those bodybuilder guys.

          • daisy says:

            Depends how you’re wired to start with. I suspect “being prone to spiritual experience” is normally distributed in the population like most other psychological traits. People to the far right of that particular bell curve are quite likely to have their normal sense of reality seriously fucked with by meditation.

          • Jaskologist says:

            I wouldn’t be sure. I’m religious, not spiritual, and I encountered the Dark Night, without even knowing it was a thing beforehand. This wasn’t through meditation, but the phenomenon exists across every religion, and probably outside of religion as well. I would surprised if even shallow but consistent meditation did not take you to the same place. Spiritual experience turns out to be quite replicable; you just have to do the standard practices consistently and earnestly.

    • theLaplaceDemon says:

      I thought that “inflammation” in this context usually means “cytokines” specifically.

      (edited for clarity)

  3. Anonymous says:

    Is ibuprofen used less in the US than in other countries? Because it’s the first thing that comes to mind with regard to OTC anti-inflammatory drugs here in New Zealand.

    • Anonymous says:

      I’m not a doctor but I’d say at WORST ibuprofen is the third-most popular anti-inflammatory in the US, after aspirin or APAP. It might be more popular than APAP.

      • Sniffnoy says:

        APAP isn’t really much of an anti-inflammatory as I understand it. Not sure it should count.

    • William O. B'Livion says:

      In NZ and Australia Ibuprofen is (IIRC) about 5 dollars (AUD/NZD) for a pack of 20. Italy was about the same price (again IIRC). In AU you could get 400mg tablets over the counter

      In the US you can get it at Walgreens for about 20 USD for 1000 200mg tablets.

      Just that alone makes me suspect that “we” use more Ibuprofen than NZ/AU/Italy.

      OTOH you could get Acetaminophen + Codeine OTC there.

  4. Anon says:

    Weed is an anti-infammatory. Checks out.

    Actually, on a more serious note, after reading this, weed sounds like the depression miracle drug: increases appetite and BDNF levels, treats insomnia and inflamation. And then there’s the euphoric effects, and I think(?) THC behaves as a serotonin reuptake inhibitor to some degree and may (more study needed) increase production [additional diclaimer needed], not to meniton that weed has a lot of different 5HT-agonists.

    • haishan says:

      I’ve, um, heard from people who totally aren’t me that ibuprofen effectively relieves many of the cognitive effects of cannabis intoxication. I just assumed that this was via some anti-inflammatory mechanism, but if weed’s already anti-inflammatory this doesn’t seem to make much sense. Is this just a placebo? Or is there something else going on?

    • Anonymous says:

      Which is funny, given that it’s literally a depressant.

      (I’m neither a stoner nor someone who suffers from depression, so I have zero first-hand knowledge of this topic. Just find it amusing)

      • Nornagest says:

        Something being a depressant in the pharmaceutical sense just means that it has a tendency to inhibit activity in some part of the CNS, just as stimulants have a tendency to provoke it. It doesn’t have much to do with depression in the psychological sense.

        • tanagrabeast says:

          I’ve found that a single 200mg pill of Ibuprofen, when taken to calm a toothache or at the first sign of an impending headache, has mild mood elevating effects on me, taking me above my normal baseline levels. It doesn’t always happen, but it happens far more often than I have been able to explain. I’m also a naturally grumpy, allergy-prone individual. So… a connection does seem possible, at least for me.

      • Kev says:

        The Cannabinoids are either their own category or they are hallucinogens.

    • Sarah says:

      I am weirdly anti-weed for my culture, and I think most of that comes down to the fact that it’s a *plant* so it does ALL KINDS OF THINGS and you never know what you’re gonna get.

      (For example, it might make you very damn unhappy, which isn’t so good for depression.)

      Lots of things have mouse or in-vitro studies showing an anti-inflammatory effect, so I don’t know how confident to be in this, but most of the “good news” about cannabis is also true of the compound cannabidiol, which *isn’t* hallucinogenic. (Anti-inflammatory, painkiller, anti-nausea, anti-epileptic, etc).

  5. Anonymous says:

    At the risk of going off-topic, I’d like to say that although they’re never as popular as your more regret-inducing posts, I’ve always been a fan of your medical, statistics, and miscellaneous (three separate categories there, not one!) posts. I appreciate you still do those despite them not giving you as much of that sweet, sweet traffic. Thanks Scott!

    • Anonymous says:

      The medical posts are always my favorites. I only read most of the (feminism/I will regret writing this) posts out of some misplaced sense of duty to read every post.

      • BD Sixsmith says:

        …some misplaced sense of duty to read every post.

        This is such a Catholic community.

        • Deiseach says:

          This is such a Catholic community.

          Scarily so at times. Speaking of which, today is the feast of Epiphany which means Scott can now legitimately use his “We Thread Kings” imagery and post title today 🙂

    • J. Quinton says:

      I enjoy these posts too. I don’t comment because it’s an educational post and I wouldn’t have anything to add.

    • JL says:

      Yeah, I eat these up and feel good about learning something afterwards. “I will regret writing this” posts are interesting, but I get a little of the dirty/regretful affect from reading them that I think Scott gets from writing them.

    • Love these so much.

    • Creutzer says:

      Joining the choir here.

      • theLaplaceDemon says:

        Same! Wish they made up a larger % of the blog.

        (though obviously Scott should write about whatever he wants, because personal blog and all)

  6. nydwracu says:

    Could this be another one of the things we think are social that turn out to be biological?

    To an extent. But the next level of contrarianism is also true. Sleep deprivation is certainly a social problem: long commutes, people staying up to watch TV, the destruction of the eight-hour workday, and so on.

    • Anonymous says:

      I never pass up an opportunity to mention society is a result of biology!

    • Harald K says:

      Yeah, my immediate thought was, “well sure, that’s the right way to frame it if you want to get taken seriously, but stuff like diet is pretty damn social”.

    • Yes. Brain chemistry is a provable cause of a lot of stuff, but then changes in brain chemistry are fairly easy to provoke with the right stimuli too. Annoying multidirectional causality!

      It feels like (or perhaps I just wish that) the trend in psychiatry is starting to move away from framing the biological factors as acasual, and instead moving towards a more complete model where it can be intergrated with a more complete human science (structural, cultural, social, psychological, chemstry, genetic). Maybe the social sciences will engage better with biology then too!

      Of course when you go looking for sound evidence of social factors to negative stuff like depression there’s a big empty space where the empirical evidence ought to be. That’s because you can’t really formulate a proper social psychology experiment on that sort of thing that’s going to have a remote change of getting ethics approval. Basically you can’t deliberately try provoke horrible outcomes for people to find out what causes bad outcomes for people (and unlike drug testing, you can’t use mice to check your expirment isn’t going to cause unacceptable harm to people).

      My favourite example is the Stanford Prisoners Experiment – no way it’d happen now, but there’s a darn good reason its taught to first year psychology students. Human behavioural experimentation seems to have a massive potential to go horribly wrong, and so I’d be waay suspicious of a proposal to change things back, but the utilitarian argument is always sitting there saying “wouldn’t you like to see these mind-blowing experimental results”.

      • fubarobfusco says:

        Given the degree to which the “experimenter” told the “subjects” what roles to adopt, the Stanford Prison Experiment is probably better characterized not as a psychology experiment but as the worst LARP session ever.

        • Jaskologist says:

          Given the population that was sampled, the Stanford Prison Experiment should really only be taken to show that all Stanford students are latent fascists.

    • Kev says:

      >>”the destruction of the eight-hour workday”


  7. J says:

    33% more than 1.5 million heart attacks would be an additional 500,000, not 50,000.

  8. Hunt says:

    One at least anecdotal data point I can add is that I know a man who recently completed hepatitis C treatment (actually, cure), which must involve a battery of anti-viral drugs. I didn’t have to deal with him during treatment, but from what I heard, he became seriously depressed, as do many other patients. Many actually drop out of treatment altogether. Since it deals with the immune system, perhaps the treatment boosts cytokine levels? It also makes me wonder about HIV antiretroviral treatment and whether there have been any studies about how it affects depression rate.

    • Anonymous says:

      Scott didn’t give an statistics or links to studies, but he mentioned this in the post. Search for hepatitis.

  9. Erebus says:

    Palmitoylethanolamide would seem to be the ideal molecule to test your theory with. It’s an orally-bioavailable anti-inflammatory substance that does not seem to irritate the lining of the GI tract, nor does its use seem associated with cardiac complications. (At this stage.) In fact, as a reasonably potent PPARα agonist, it might actually reduce lipid levels and improve cardiovascular health.

    There is some evidence that it works as an antidepressant in mice. (More evidence: 1, 2) This, naturally, has already led to some theorizing — “is there a role for palmitoylethanolamide in the treatment of depression?”

    Having said that, we can’t rule out the possibility that palmitoylethanolamide is neuroactive in a way that has little to do, strictly speaking, with its activity as an anti-inflammatory agent — e.g. as an endocannabinoid, or by modulating neurotransmitter levels.

    …So to really test your theory, we’d want two anti-inflammatory compounds. One that crosses the BBB and reduces neuroinflammation without any known or observed psychopharmacological value. Licofelone might work. Then we’d want another that doesn’t cross the BBB at all. An anti-inflammatory peptide. Then, of course, a true placebo group.

  10. I don’t understand how depression could turn out not to be a psychological phenomenon. Like, don’t we know that certain personality types are more prone to depression, e.g. creative people? And don’t we know that certain interventions like electroshock therapy and ketamine can cure depression by “resetting” the brain? And like, yes, sometimes depression just comes out of nowhere, but also a lot of the time it genuinely does come after a sad event like death, divorce, job-loss… right? Am I missing something here?

    • Anonymous Utilitarian says:

      If depression is an adaptation, it may be triggered by different things. Scott starts out by observing that (mild) depression may be triggered by sickness. Likewise, it may also be triggered by intense sadness (or, injecting some B.F.Skinner, both the sadness and the depression are triggered by a stimulus.) There is at least one theory of adaptive depression that posits a kind of social bargaining function of depression: You may get depressed if you can’t get out of an exploitative situation. Depression temporarily withholds your services to the exploiter, maybe getting you a better deal, somewhat like a labor strike.

      • Peter says:

        “like a labour strike” – people might like to know about John Nash’s “minds on strike” idea. This comes from a person who a) was one of the founders of Game Theory and b) spent about three decades in and out of mental hospital with paranoid schizophrenia. It’s googleable for, although the things you get are a bit bitty.

        Of course, if you want to suggest that mental illnesses are adaptive, or adaptive in some cases, or have adaptive aspects in some cases, then you should wonder whether psychiatric medication is adaptive too. I suppose it depend on how much credence you give to the various things one hears about pre-scientific herbal medicine, self-medication in non-human animals, etc.

    • Tracy W says:

      Why would we expect what happens in our mind to be clearly separate from what happens in the rest of our body?

      Anyway, maybe depression is a social construction in the sense of it being our word that we slap on a bunch of symptoms that are actually similar-looking outcomes of very different underlying processes.

      • Ptoliporthos says:

        I agree, clinicians often fall into the trap of confusing the symptoms with the disease. Depression is probably another one of these regrettable incidents.

        Many common syndromes have a heterogeneous set of underlying genetic and biochemical causes, like cancer, heart disease, or diabetes. I suspect that psychiatric disorders are especially prone to being inappropriately combined into syndromes with heterogeneous biology, because brains are complicated and psychiatrists can’t biopsy them to see what’s actually wrong. It would be nice if psychiatric diagnoses were on some sort of firm material quantitative basis, like “your serum serotonin levels are 2 s.d. below normal” or “you have high levels of cytokines” or “the MRI shows this region of your cortex is smaller than average,” but things are mired in the very subjective Freudian mode of “sit down and tell me about yourself and I’ll try to match what I hear to some patterns I have seen before.” I know that it’s a hard problem, but the current approach to psychiatric diagnosis has some very obvious failure modes, one of which is lumping cases together because the symptoms seem similar, then making a hash of the underlying biology when you do association studies.

        The idea of “the autism spectrum disorders” is an example of this tendency run amok. The term has enabled a pervasive doublethink that allows researchers to pretend they’re acknowledging heterogeneity while they inappropriately pool their cases for an association study as though they were homogeneous. I understand the temptation, because where are you going to get 100,000 patients of one ASD subtype for an appropriately powered study, but what use is an association study where you pool several, potentially genetically unrelated disorders? You get unhelpful findings , like cases have more differences from the reference genome than controls, but no one gene is significantly different.

        There’s a fascinating article showing how schizophrenia may break down into 8 different syndromes each with heterogeneous genetic causes (link to press release with link to article). Perhaps broader application of Non-negative matrix factorization could rescue some existing psychiatric GWAS data, but I’m not optimistic that most diseases would have enough objective diagnostic criteria to break them down into consistent subtypes across big multinational patient recruitment consortia.

      • stillnotking says:

        I’m personally convinced that what we call “depression” is a grab-bag of multiple disorders, if for no other reason than that there are so many plausible etiologies and treatments for “it”. In some people it’s learned helplessness; in some people it’s serotonin imbalance; in some people it’s probably inflammation. I know from talking to others who have suffered depression that the subjective experience is quite varied. Hell, just look at the DSM list of symptoms, some of which are literal opposites (insomnia and sleeping too much).

        Of course these disorders may overlap and reinforce one another, but it seems doubtful we’ll ever find a one-size-fits-all remedy for “depression”, in the way we quite possibly might for schizophrenia, autism, etc.

        • Mary says:

          Like diabetes. Which, with hindsight, is a syndrome actually caused by two completely distinct diseases.

    • theLaplaceDemon says:

      I don’t know about electroshock, but the mechanism by which ketamine is antidepressant is definitely not known yet (same is true for other antidepressants too, but the lit is even smaller for ketamine).

    • Scott Alexander says:

      Stress contributes to heart disease as well. In a biological sense, (vast oversimplification approaching) equals the hormone cortisol, which has all kinds of effects. It’s perfectly possible for cortisol to affect physical diseases.

      As for ECT, ketamine, etc, analogy time. Imagine that sinister conspirators are putting liquid Ativan (a sedative drug that affects brain receptors) in the water supply. As a result, you keep drinking water and then getting woozy, tired, confused, et cetera.

      A doctor discovers that giving you flumanezil, an antidote to Ativan, treats your unexplained syndrome.

      Now, in one sense, we know the problem’s “in your brain”, since a drug that affects brain chemicals cures it. On the other hand, it seems fair to say that an attempt to discover the true root problem should start by looking in the water supply.

      Does that help?

      • Not That Scott says:

        Only tangentially related, but… if exercise, good diet, good sleep, etc are recommended because (in part or whole) they reduce cortisol levels, is there a more direct way to reduce cortisol levels? (Looking up `dexamethasone overdose treatment` and `dexamethasone interactions` didn’t suggest anything to me)

        Then again, I feel like a medication that lowers cortisol levels would be pretty well-known.

  11. Murphy says:

    “Inflamation” is a bit of a vague catch all but I’d be interested if people with dermatographism suffer increased rates of depression.

    I know antihistamines make me a much more cheerful person but I prefer to put that down to the fact that they also make me a much more pain-free person who can breath easily.

    • matt h says:

      Hmm…I’ve had this, and every other type of allergy since I was a kid, never been depressed. I’d like to know too if that’s typical, or are they comorbid.

  12. John Maxwell IV says:

    I noticed that getting stressed out seemed to aggravate my sickness when I got sick. If stress aggravates sickness, then calm should relieve it, right? So I started taking anti-anxiety supplements like theanine, inositol, chamomile tea, ashwagandha, etc. when sick. Seems to work decently well.

    These studies are pretty interesting: Supposedly taking garlic on a daily basis reduces the incidence of sickness quite considerably.

    Discussion of low-dose aspirin consumption on LW:

    • D_Malik says:

      Spent some time (probably 45 minutes each) looking into these. My conclusions, which might save other people some time:

      * Low-dose aspirin: The cost-benefit difference seems to be close, but still slightly in the red if you’re ~20 years old like me. I’m planning to look into this again in my late 20s. If you’re older than 30 or 40, you should look into it.

      * Garlic seems like a very good deal. Taking 2.5g of garlic extract daily probably reduces total time sick with the common cold by ~85%. You can get garlic pretty cheap, say $20 for a 3-month supply. 2.5g is too much to take in capsules or tablets, rather buy some powder and throw a teaspoon on your food once a day.

      • D_Malik says:

        Parent comment made some mistakes about garlic. Consuming 2.5g garlic daily reduces time sick by ~70%. In convenient capsules of aged garlic extract, that’ll cost you around 0.50 USD per day. Both studies linked by Examine are pushing specific supplements. The first study is pretty suspect. The second study is much less suspect, and is pushing Kyolic brand aged garlic extract supplements. All things considered, 2g daily of the Kyolic (or a cheaper knock-off) is likely worth it, though it depends on how valuable your time is and how often you’re sick.

  13. haishan says:

    But levels of inflammation are also increasing over time, probably because we have a terrible diet that disrupts the gut microbiota that are supposed to be symbioting with the immune system.

    So do you, Scott, think there might be gut-floral and cascading benefits to eating like our ancestors? And I’m not even talking about paleo; could we be a lot healthier if we just ate like eighteenth-century peasants?

    (This is not a request for medical advice, I’m aware Scott isn’t an expert in this stuff, etc., etc.)

    • Anonymous says:

      “Paleo”, by the way, is nonsense; people in the actual Paleolithic did eat their share of grains and legumes; there’s plenty of evidence of that.

      • haishan says:

        There are people like Stephan Guyenet and, to some extent, Loren Cordain, who understand this; there are also lots of people who don’t. I’m speaking more of the former.

        • Just another commenter says:

          +1 on Guyenet. Here are some good links to get you started if you want a quick brain dump.

          One of the things he observed was the egg-retrieving behavior of the greylag goose. When an egg rolls out of a goose’s nest, it gently uses its bill to roll it back in. However, when Lorenz took an egg from the nest and placed it next to a larger round white object, the goose preferentially rolled the larger object back into its nest while ignoring the real egg. He called this larger object a superstimulus. […]

          Your brain is pretty simple in some ways. It has these very basic hard-wired associations, like “sweet is good” and “free glutamate is good”. If your brain likes a little bit of sweet, then it really likes a lot of sweet. If it likes a little bit of glutamate from meat, then it really likes a flood of glutamate from MSG. Just like the graylag goose that prefers the big white ball over her own egg, your brain drives you to ignore normal stimuli in favor of more potent superstimuli.


          t all started with one little sentence buried in a paper about obese rats. I was reading about how rats become obese when they’re given chocolate Ensure, the “meal replacement drink”, when I came across this:
          …neither [obesity-prone] nor [obesity-resistant] rats will overeat on either vanilla- or strawberry-flavored Ensure.
          The only meaningful difference between chocolate, vanilla and strawberry Ensure is the flavor, yet rats eating the chocolate variety overate, rapidly gained fat and became metabolically ill, while rats eating the other flavors didn’t (1). Furthermore, the study suggested that the food’s flavor determined, in part, what amount of fatness the rats’ bodies “defended.”

          Food Reward: a Dominant Factor in Obesity, Part I

      • Scott Alexander says:

        I don’t know too much about this, but the best paleo I know of focuses on modern wheat products in particular rather than carbs in general. I know some paleo diets that say have as many potatoes or rice or cassava or whatever as you want, just stay away from wheat and refined sugar. I don’t totally agree with this (I’m not in the boo gluten camp) but at least the paleoanthropology seems to check out.

    • Anonymous says:

      >could we be a lot healthier if we just ate like eighteenth-century peasants?

      Eighteenth-century peasants ate horrible (disclaimer: based on current medical science and not universal truth!) diets probably more removed from our hunter-gathered ancestors than our current diets.

      That said, I recall hearing your idea somewhere else so I’m inclined to think it’s at least worth exploring.

  14. matt h says:

    So how does Scopolamine rapid anti-depressant effect fit in to this picture?

    • Erebus says:

      It’s a neurotransmitter modulator, and a bit of a blunt tool, at that. The working hypothesis is that scopolamine is more than just an antimuscarinic agent — it’s also an NMDA receptor antagonist. In the context of our gracious host’s post, it might be worth mentioning that BDNF is downstream from there; it seems as though NMDA receptor antagonism leads to increases in brain BDNF levels. This may be relevant. Then again, as NMDA antagonism affects a million other things & as NMDA antagonists are used recreationally for their rapid-onset euphoric and disassociative properties, BDNF may have very little to do with the effects of scopolamine.

  15. Daisy says:

    Only sharing this anecdote because it’s timely: the last few days I have been taking very large doses of flaxseed oil (2-3 tablespoons, the bottle says to take 2 teaspoons per day) and it’s had a massive effect on my mind.

    It honestly feels a little weird and almost uncomfortable; I have a lot of depressive symptoms but my usual subjective experience is of dissociation, not depression. But now I suddenly feel hyper-aware of my body, and like I weigh a ton. Which is what groundedness feels like to a person who dissociates all the time. And I seem to have more motivation to get stuff done. It’s quite different from my usual experiences of motivation, which occur when I’m sufficiently stressed or excited or needed by another person to find an external motivation.

    That wasn’t even my purpose in taking the oil; I am trying out the Shangri La diet to lose Christmas flab, and I thought I might as well use an oil with bonus anti-inflammatory health benefits. (The weight loss part of it also seems like it will work for me, in case anyone’s collecting anecdata on weird body hacks. You drink the oil with nose clips on so you can’t taste it, which is supposed to activate an appetite suppressing mechanism, and so far it does. Feels super goofy but at this rate I will definitely keep doing it.)

  16. MikeH says:

    I know you’re fairly skeptical of nutraceuticals, but I wonder if things like Curcumin may give people much of the anti-inflammatory benefits without the drug risks.

    Fish oil helps depression on occasion as well, if I remember correctly.

    • Anonymous says:

      why would it lack the drug risks?

      Pretty much everything has side effects in high enough doses or if you watch enough people for long enough. Things which are biologically active but only biologically active in the ways you like are rare.

      • William O. B'Livion says:

        I had a weird Tai Chi instructor years ago who insisted there was no such thing as “side effects”. There were effects, *period*. Some of them you wanted, some of them you didn’t, but sometimes they were different manifestations of the same thing.

    • JadeNekotenshi says:

      I wouldn’t say “no risks” so much as unknown risks. Any chemical that alters biochemistry is a drug, to oversimplify slightly, and all drugs have side effects. Of course, some of those side effects may be very minor, secondarily beneficial or ludicrously rare.

    • Scott Alexander says:

      I’m not especially skeptical of curcumin. There are good studies backing it.

    • Mike H says:

      It was a poor choice of words. People can definitely get side effects from things like curcumin. They tend not to be as bad as drugs, but the effects tend to be much less too. I see these quasi-drugs as potentially low risk/moderate reward on average, at least for the the best examples like curcumin, fish oil, and I’d argue Vitamin D.

  17. onyomi says:

    Single crackpot theory-that-explains-everything time!

    I think a great many of the most common modern health problems can be traced in some way to lack of balance between the starving-fed axis. In the past, people would naturally suffer through lean times. Even in a good year, it probably wasn’t unusual to have one particularly rough week in winter when you basically got nothing.

    Fasting not only makes you less fat, it’s strongly anti-inflammatory. In my experience, it also helps with mental problems like anxiety and insomnia. Eating a lot (or even a “normal” amount, by today’s standards) sets off a whole bunch of processes that basically seem to say, “work! play! have sex! fight! now’s the time!” Fasting sets off the opposite signals: “rest, recover, conserve, etc,” though I believe it also increases some stimulating things like norepinephrine also known to help with depression.

    It may sound like, if you’re depressed, you need your “live! fight! love!” circuits activated, but I think there is also such a thing as having your “live! fight! love!” circuits burned out due to over-stimulation, like how type ii diabetics have plenty of insulin, but it stops working.

    If everyone spent five days (in a row) consuming only water once a year, I think we’d see a big improvement in a lot of problems (this comes from my own experience doing so).

    • Brad says:

      Isn’t fasting recommended in a number of religions? I know it is in Christianity, even if it seems like it’s not emphasized as much in American Protestantism (I cannot speak for Catholics or Orthodox Christians). I don’t want to conflate a spiritual effect and a physical one too much here, however.

      • Jaskologist says:

        It is recommended by basically all of them, with the notable exception of the Sikhs.

        • onyomi says:

          Yes, indeed. And this is because it’s good for your soul! It can’t be a coincidence that basically every world religion came up with it independently or semi-independently.

          And it’s not because being hungry causes you to suffer religious hallucinations or something. Actually, one generally feels greater lucidity and groundedness during and after a fast.

      • Jaskologist says:

        On the topic of universal religious practices, I considered it a while back and came up with 3 that are found everywhere even though they have no clear temporal benefit.

        -Fasting, as mentioned already
        -Prayer/meditation: Not strictly the same thing, but they exist on the same spectrum, from outward to inwardly focused, and I found that while different religions will emphasize one more than the other, they still include both forms.
        -Sacrifices: back in the day, everybody did human sacrifice. Half of the OT is about how hard it was to get the Israelites to stop sacrificing their infants. Animal sacrifice was also huge, and to this day, if you visit Taiwan around their New Year, you’ll see businesses burning (fake) money as an offering.

        Notably, the human feeling that sacrifice is required seems to have faded a lot from ancient days.

        Also notable: if I had to guess at something that would be widely considered to give spiritual insight, I would have gone with hallucinogenic drugs. But you really only find that in the minor tribal religions.

        • Jaskologist says:

          I just realized that I should add another one: the Dark Night of the Soul is experienced by *all* serious religious seekers.

          • Mary says:

            I think on this topic I will instead continue to believe the guy from whom we get the very term “dark night of the soul.”

            “This night, which, as we say, is contemplation, produces in spiritual persons two kinds of darkness or purgation, corresponding to the two parts of man’s nature—namely, the sensual and the spiritual. And thus the one night or purgation will be sensual, wherein the soul is purged according to sense, which is subdued to the spirit; and the other is a night or purgation which is spiritual, wherein the soul is purged and stripped according to the spirit, and subdued and made ready for the union of love with God. The night of sense is common and comes to many: these are the beginners; and of this night we shall speak first. The night of the spirit is the portion of very few, and these are they that are already practised and proficient, of whom we shall treat hereafter.”

            The dark night of the soul is, of course, the dark night of spirit, not sense.

          • Jaskologist says:

            Yes, I suppose I’m actually only referring to what St. John of the Cross called the Dark Night of Sense. It seems like the common usage does not make such a distinction, though.

        • onyomi says:

          I happened to be at a Hindu temple today and, thinking about all the offerings of food left in front of all the deities, it was clear to me that this was a form of sacrifice, though it is conceived more in terms of an “offering.” The Hindus would likely classify it as a form of “bhakti” or devotion, and I think that that is actually the key for efficacy. The human brain does well when it can devote itself to some ideal–be it a cause, a goal, or the image of some god. Sacrifice is one way of enacting dedication.

        • Anonymous says:

          “Notably, the human feeling that sacrifice is required seems to have faded a lot from ancient days.’

          Well, the Catholic churches still have the One Sacrifice, every Mass, but I would point to Christianity as the most likely culprit.

          It’s been so thorough that if you ask a neo-pagan which religious rites are mandatory, in particular what sacrifices, or how to determine whether a god is offended by you and what sacrifices to make to appease said god — things universally found in paganism — they often don’t even fathom the question.

        • “Half of the OT is about how hard it was to get the Israelites to stop sacrificing their infants”

          It is? Could you supply some quotes? I thought there was a lot about getting Israelites to stop sacrificing to idols, but that’s hardly the same thing.

    • William O. B'Livion says:

      I’ve done intermittent fasting in the past (and will probably start back up once the cold is over for the winter), and frankly the Fight! part is *MORE* likely when fasting. When I used to do 24 hour fasts I carried around a food bar of a kind I didn’t particularly like just in case I needed to deal with something stressful after 22 hours of no food.

  18. Andy Harless says:

    You talk about “good diet” as if it were generally agreed what that means. With some nutrition scientists recommending Americans eat more carbs and less fat, while others recommend they eat less carbs and more fat, I have some trouble with the concept of “good diet.” Most seem to agree that typical Americans should have more fiber and a greater proportion of omega-3 fats, but that’s not really much to go on (especially since it’s pretty easy to go well over recommended fiber levels if you try — I know from experience — and you can supplement by taking lots of fish oil pills, etc, but I’m doubtful as to whether this really helps matters, in that fish breath and flatulence probably have a negative impact on mental health).

    EDIT: Oh, the other thing nutritionists seem to agree about: added sugar is bad. Fine, except that it makes no sense at all. Fruit (most, but not all, nutritionists say) is good for you, but if you take the fruit apart into its components and then reconstitute it, it now has “added fructose” (the same chemical in the unspeakably evil HFCS, excuse me while I cross myself and beg God’s forgiveness for even typing the initials). Or shall we compare a large baked potato (vegetables, yay!) along with a large serving of brown rice (whole grains but without all the gluten, yay!) to a commercial nutrition bar containing a substantial amount of added sugar (along with, quite plausibly, more fiber than the rice and potato). It’s been years since I took biochemistry, but I know enough about the Krebs cycle (ha ha) to have a really hard time believing added sugar is really what one should be worrying about in this choice.

    • Cadie says:

      The problem with added sugar isn’t directly that it’s added, it’s that it’s extra sugar on top of a diet that is probably already laden with sugar and refined starch, and foods with lots of extra sugar correlate closely to heavily processed superstimulus and junk foods. “Don’t eat many foods with added sugar” is basically a heuristic to help steer clear of some kinds of junk food. Not all added-sugar foods are unhealthy, and certainly plenty of foods that don’t have it should only be eaten infrequently for best health. But it’s a simple guideline that does tend to improve the quality of one’s diet.

      • Andy Harless says:

        It’s not such a simple guideline really, because it’s very hard to determine how much added sugar a food has. The label will usually give you total sugar, which by itself is useless AFAICT, and you can see where the sugars come on the list of ingredients, but then it becomes mostly guesswork to decide how much total added sugar it implies (since sugar is seldom the first ingredient, and many foods contain more than one kind of added sugar, and anyhow perhaps the average person shouldn’t be expected to have enough expertise to figure out which ingredients count as added sugar, let alone trying to do the precarious mapping from multiple ordinals on the list of ingredients onto a single quantity).

        In principle, I suppose the FDA could require disclosure of the amount of added sugar in products, but requiring such disclosure would just provide an opportunity for gaming the system. If everyone decided that added sugar was bad, food producers would figure out how to produce unhealthy foods that have less added sugar, and the guideline wouldn’t work any more.

        So I continue to maintain that the recommendation to “eat less added sugar” doesn’t make any sense. If you have an idea of what’s actually healthy, it should be just as easy to apply as this guideline. (But then, as I said before, there’s little agreement about what’s actually healthy.)

    • Anonymous says:

      There is more to digestion than biochemistry, as you admit by your mention of fiber. But fiber is a broad category. Has there been any study of the glycemic index of fruit vs juiced fruit, with all pulp included?

    • Scott Alexander says:

      You know how I always say “You don’t need a complete theory of ballistics to stop shooting yourself in the foot”?

      The problems with most people’s diet are way before the point where nutrition-related debates start kicking in. Stop eating so many Twinkies and then we can talk about the low carb versus low fat versus low calorie debate.

      (not necessarily aimed at you, just my general opinion on this)

      • Andy Harless says:

        I think the debates kick in immediately, because what (if anything, but see below) do you replace the Twinkies with? (Let’s assume calorie-for-calorie replacement as a baseline.) Some would say it’s just fine to replace them with extra cream in your coffee and eggs fried in bacon grease. A little more conservative would be to replace them with nuts and seeds (but FWIW in my experience, when I tried replacing carbs & animal fats with nuts, my triglycerides and A1C both went up). Some would say replace them with fruits, vegetables, and whole grains, but the bacon grease enthusiasts would be just as horrified with that (Too many carbs! Gluten is evil!).

        Now you could say just replace the Twinkies with nothing at all, but that doesn’t really solve the problem. It’s pretty well established, I think, that, for most people, suddenly and arbitrarily reducing you calorie intake, without any kind of plan for how you’re going to maintain the lower intake, does not, in the long run, typically result in a healthier diet. If you want the Twinkie removal to be a long-run constructive change, you need to look at the rest of your diet and figure out what you’re going to be willing to stick to. And then we’re back to the debate: “Fiber is filling: eat whole grains and fruits!” “No, only fat will make you feel satisfied!”

        Now perhaps the generic “good diet” (before we get into the specific debates) just refers to any eating tendencies that have allowed someone to successfully maintain a healthy weight. But in that case, I have trouble seeing the causation as running from diet to mental health. Having a “good diet” in this sense is more a symptom of a certain type of mental health than an effect of merely being well-informed and intelligent in ones choices. (I mean, it could be the latter, but then we’re back to the debates about what information it is that causes people to have a successful diet.) “Good diet” in this sense might be associated with less depressive tendencies, but the most plausible explanation IMO would be that the conditions that lead to depression also lead to unhealthy eating (and those that lead to recovery also lead to healthy eating).

        • anon1 says:

          There’s an obvious default here: increase, proportionately, your intake of all the non-Twinkie foods you were eating before until you’re getting the same number of calories. It would be hard for that not to be an improvement.

      • Is that less sugar or just less calories more generally?

    • William O. B'Livion says:

      Go to the juice aisle in your local store. Read the ingredients.

      WTH are we adding *sugar* to things like apple and grape juice?

      • Andy Harless says:

        Still, the heuristic there should be, “Don’t take in a lot of carbs at once, especially in liquid form, especially without fiber, especially without other foods.” If people followed this heuristic, they would choose not to buy juice with added sugar (or would choose to drink only small amounts of it and in combination with other foods, which is fine), and they would also choose not to eat a meal containing large servings of rice and potatoes washed down with unsweetened fruit juice, which I expect is actually a lot worse that drinking a little bit of sweetened fruit juice.

        (Though, of course, if one happens to be one of the people who thinks carbs are just fine and fat is the root of all evil, then this heuristic might be irrelevant, but then it becomes difficult to explain why added sugar is bad in the first place.)

      • nydwracu says:

        It’s hard to find unsweetened kefir. Why are people adding sugar to something that’s basically milk?

        • Nita says:

          It sounds like you live in the USA, and Americans seem to be suspicious of cultured milk products (except cheese).

    • Just another commenter says:

      Andy, the links I provided above will give you insight into added sugar. You are correct that there is nothing wrong with sugar per se. What’s really a problem is what it does to the brain’s reward system. Your brain’s reward system evolved to deal with the amount of sugar in fruit. It did not evolve to deal with the amount of sugar (combined with fat) in donuts and ice cream. Donuts and other yummy treats act as a superstimuli that get around the body’s homeostasis mechanism.

  19. Sarah says:

    I have a very specific feeling after inadequate sleep, which is something like “pressure in my head.” (it’s too mild to really count as a headache.) And my brain interprets that pressure as “time for emotional distress!” It took me years to figure it out, but I feel despair if-and-only-if I’m sleep deprived (and having six hours of sleep instead of seven is enough to do it.) I had a highly unpleasant “depressive episode” years ago, and I’m pretty sure that my problem was almost entirely due to inadequate sleep.

    I suspect that the “pressure” feeling is just plain inflammation. But aspirin doesn’t do a damn thing for it. Only actual sleep works.

    • theLaplaceDemon says:

      I have something sort of similar. Lack of sleep makes me perceive things very pessimistically – like, I think the reason someone didn’t email me back is because they’re mad at me, not because, you know, they’re busy and my email wasn’t time sensitive.

      • nydwracu says:

        Lack of sleep makes me introverted, at least in part by a similar process.

        (I don’t think it’s “lack of sleep” so much as some combination of “being woken up by an alarm” and “waking up later in the day” — I woke up at around 6:30 this morning after sleeping for six hours and getting woken up by melatonin dreams* and I’m fine, but if I get eight hours and my alarm wakes me up at 8:30, everything is going to be terrible.)

        * I used to be able to take the default-sized pill, but now I have to break them in thirds or so.

        • Anonymous says:

          There’s no such thing as a “default” dose of melatonin. Maybe your pharmacy switched from stocking 1mg to 3mg or 3 to 10. I recommend the smallest dose you can find, though I haven’t tried anything smaller than 0.1mg.

  20. Your mention of injecting TNF-a in rats rang a bell for me. I have Crohn’s disease and take a drug called infliximab, which is an anti-TNF-a antibody. Looking on Google Scholar I found the following two articles:

    Basically, infliximab works on depression in people with ankylosing spondylitis (a terrible inflammatory disease with a delightful name) but not in people with major depression but no comorbid . This seems like a nail in the coffin for the idea that TNF-a is a primary cause of depression.

    • Scott Alexander says:

      Very interesting. I think the inflammatory camp would argue there are lots of cytokines, and TNF-a may cause depression in some cases but not others.

  21. Anonymous says:

    New subtitle idea for this blog: The Post-Last Psychiatrist.

    • Anonymous says:

      Have you seen the comments there recently? The place has gone to hell without Alone.

      • pthagnar says:

        did you ever find the comments to TLP worth reading? i don’t think i ever have; at least nothing sticks in my mind from having done so [except the fellow with the LAW SCHOOL IS A SCAM blog]

        • Anonymous says:

          It’s funny you mention the law school poster; that one and johnny are the ones I remember. The older posts had better comments.

  22. Pasha says:

    I am surprised you don’t mention massage in either this article or the blog linked at the end. Personally i find that has been one of the best short-term ways to uplift my mood. This may be particularly good for men, who might suffer from “touch deprivation.”

    • Anonymous says:

      This may be particularly good for men, who might suffer from “touch deprivation

      From personal experience, I suspect that practicing social dancing and grappling arts can also work by pretty much this mechanism.

      • Nornagest says:

        Also from personal experience, if touch deprivation is a thing, I doubt that grappling arts do much for it: the psychological context of e.g. hugging someone is very different from the psychological context of e.g. clinging to someone’s back while trying to choke them out, even if the total amount of body contact involved is about the same.

        • Anonymous says:

          In a way yes, but usually once you break the initial barrier to touching other humans at all platonic touching also becomes psychologically easier. Helping people up off the ground, slaps on the back, just more physical closeness based on the initial okness of being able to touch those people often follows.

        • Anonymous says:

          nornagest, you might be right. I remember seeing a piece in the Pacific Standard or somewhere like that suggesting that part of the popularity of BJJ was due to just this, but I can’t find it now and it was the Pacific Standard (or Popular Science, or something) anyway, so meh.

  23. Wirehead Wannabe says:

    1) My subjective experience of being sick is nothing like my experience of depression. Sluggishness is about the only symptom the two have in common. Do other people feel the same, or am I atypical?

    2) If it was all inflammation, why does talk therapy work? Why does forcing myself to interact with friends work?

    • Anonymous says:

      Depression is a lot like sickness for me, which I suspect is part of the appeal of the cytokine theory.

      Being around friends helps because contagion behavior is self-reinforcing, at least when rationalized. Talking to a therapist helps because you realize you’re not actually sick in the “powerless, contagious” way you body is convincing you you might be.

    • JohannesD says:

      I was just about to comment that for me, being depressed has always felt quite a lot like having a flu, just without the “surface” symptoms like a running nose. The basic “feeling awful” sensation feels very similar, as does the feeling of having no energy to do anything.

    • theLaplaceDemon says:

      For your second point, it could be that someone’s unhappiness/anhedonia/etc. is from combination of life-related things and depression caused by high inflammation. Dealing with the life-related stuff sufficiently reduces the person’s unhappiness etc. such that the inflammation-caused parts are less of a big deal in terms of their overall quality of life.

      It’s worth remembering that there is no treatment for depression that works for everybody. One person may only respond to talk therapy, another may have zero response to therapy but be great on an SSRI, and another may need a tricyclic. Some people have depression that is totally treatment resistant. So it could be that the cause of depression is heterogeneous, or have overlapping causes that are weighted differently in different individuals. I don’t have a cite for this, but a person I trust to be accurate and up-to-date on the subject told me a couple years ago that a not-insignificant portion of the depressed population did not have increased cytokine levels (though increasing cytokines does seem to reliably make people depressed, as Scott mentioned).

      Also, interacting with people – especially people you feel close to – trigger its own set of neuromodulators and hormones, so it could be that those are helpful in treating depression.

  24. Daisy says:

    Talk therapy works by changing how you see the world. You see and interpret the world differently, you’ll experience it as less stressful and your body won’t produce inappropriate stress responses so often. Presumably this then leads to lower inflammation.

    I’d also presume that chain of causation also sometimes works in reverse: from lower inflammation–>fewer physiological stress responses–> less experience of life as stressful–>different view of the world.

    As for friendship: love, caring and feeling cared for are very powerful coping mechanisms for stress! (Sorry for that horribly reductive sentence. I do know they’re more than that.)

    edit: ugh, badly nested reply. Was responding to WW@3.57pm

  25. Jeff Kaufman says:

    What about fibromyalgia? It’s associated with depression but not inflammation, right?

  26. Emlin says:

    I was recently diagnosed with ankylosing spondylitis and I started tnf-alpha inhibitors… I think you have convinced me to also actually start taking my indomethacin though and see if my mood improves.

    • Scott Alexander says:

      There’s no great evidence that indomethacin treats depression, but there is some evidence that withdrawal from indomethacin causes depression. I dunno. I’d recommend taking whatever your doctor told you to take.

      • Emlin says:

        Oops, I probably should have been more clear – I’m talking about finding more compelling motivation to do what my doctor told me to do, which I’ve been doing a poor job of complying with so far. Because somehow the idea that long-term inflammation might be psychologically negative works better for me than the actual back pain to make me take the darn medicine. I am perhaps weird. That’s a really interesting study though and I will keep in it mind if I get switched to something else at some point, thanks 🙂

  27. Pingback: Depression as maladaptive sickness behaviour | nickelbook

  28. Muga Sofer says:

    >Radley Balko’s terrifying civil liberties predictions for 2015, with the world’s most obvious twist ending.

    Haha, I got to horrify my family with one of these in casual conversation. Useful!

    … well, not very, but still.

  29. Pingback: Monday Miscellany: Fish Oil, (in)Flammation, Fantasy | Gruntled & Hinged

  30. Pingback: Chronic Psychitis | Neoreactive

  31. Anonymous says:

    Wouldn’t steroids and NSAIDs also affect depression under this model?