We're a little crazy, about science!

The mechanisms of depression

Art by the incredibly talented DestinyBlue

In news that will surprise almost zero depressed people, we are once again adjusting our thought process on what causes depression. But in an effort to stave off bad advice, people telling you to stop taking your medication, and just general confusion, let’s do what we do best and talk it out. First, let’s be clear, don’t stop taking your meds, it’s never a good idea, I promise, 10 out of 10 times it’s a bad idea unless you’ve spoken with a doctor or are having serious side effects. So let’s talk about the latest news, shall we?

A study recently came out that apparently has been picked up by a lot of news feeds. So many I’m seeing it on twitter, google is recommending it to me, etc. This makes me nervous because you get stuck with horrible sounding titles created solely so you click on the thing and read the article, except those headlines are full of crap and you shouldn’t listen to them, I mean haven’t we learned anything in the least decade or so? Apparently not. In short, don’t panic or keep calm and keep taking your meds.

So what’s the study, why is it important, and what do we do now?

First, good news, the study doesn’t mean your meds don’t work. If you’ve found relief from your symptoms (even minor relief) then you’re in luck. This study doesn’t change that, you won’t lose your medication, and aside from scammy people trying to sell you overpriced water or diets, no one should suggest otherwise.

The study is what we call a meta study and in the scheme of scientific research meta studies are basically the highest standard of study because they collate other studies and look at the particular topic as a whole. That’s what this group did and that’s not actually a bad thing. Science is self correcting, we don’t always get things right and it’s actually a good thing that we change our process in the face of new and better evidence. Now what did they find?

The paper in question included 17 studies (from 360 screened) and found that, to quote the study directly,”… there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity. Most studies found no evidence of reduced serotonin activity in people with depression compared to people without, and methods to reduce serotonin availability using tryptophan depletion do not consistently lower mood in volunteers.”

It’s not a shocker really. The idea that low serotonin causes depression probably (almost certainly in my opinion) is false. This isn’t super groundbreaking really, we have seen MRI scans and found the brain almost literally eats itself, I’ve written about depression research in the past (here for example) and generally speaking the study, being a meta study, is simply agreeing with what other researchers are saying and have been saying. The brain is more complicated than a single hormone being outside a certain range. This shouldn’t be surprising to anyone who studies the brain, or even people with a working understanding of how complex the brain really is.

The really interesting thing, in my opinion, the paper found was that not a lot of high quality studies have been done. This was part of the reason the meta ankylosis got cut to 17 studies, but a review of them found that 11/17 weren’t “high quality” studies based on the metrics they used. That to me is the more shocking bit of the paper. It really suggests that we should be studying depression more and finding different ways of determining the root cause. There are so many different modalities we could use to study the changes in the brain from fMRI to EEG, it’s hard to imagine that we couldn’t find other biomarkers that would point to at least part of the cause and potentially better ways to treat it.

Now does this mean that your medications are bullshit? No. Truthfully we don’t understand the brain, we don’t really understand how the medications interact with the brain, and frankly the fact that there are so many side effects with SSRI’s and the such just proves that there are far more changes in in the brain than just increasing serotonin.

What it suggests is two things. The first is that there are different types of depression with (possibly/IMO probably) different mechanisms of action, which is why treatment is so difficult. The second is that people find relief from their symptoms with these medications because there’s some downstream or off target effect that is treating the cause, if only minorly. Again, the high chance of side effects also prove that most of these meds aren’t targeted.

This is good news for a lot of reasons, the major one is that we don’t have to start from square one, we could (in theory) design a study looking at people who respond well to medication and those that don’t. Learning the differences between the two groups could help either uncover different types of depression or lead to the discovery of why these medications actually work for depression in the first place.

Studies like this remind me of my modafinil story (here). I have a very serious and hard to treat case of depression. It’s exhausting and while I can (mostly) manage my symptoms these days, I’m literally left feeling exhausted and hurting. Like breathing is painful hurting. By chance I was prescribed modafinil a decade or so ago and suddenly the world was in color. Like literally colors looked more vivid, I felt present, awake, but more importantly it was the most normal I had felt in my entire life. Then it was taken away and for the last ten years or so I’ve been fighting to get it prescribed again. Just recently I finally got it prescribed and while it’s still at a far lower dose than I want, I still find substantial relief.

But the catch is it’s not for depression. Or at least that’s what I keep getting told even though studies suggest my outcome isn’t uncommon. I’m telling you this story because while people do and WILL use this study to drive despair and to sell their own “cures” to desperate people, I want to tell you the truth.

This is good news!

It is, because the more evidence we have to show that we don’t fully understand the mechanisms of depression the more we can focus on finding those mechanisms. This probably (almost certainly) won’t stop people from researching serotonin as the cause, but it will hopefully make others switch gears and look elsewhere for other targets and better treatments.

Science isn’t perfect, it’s simply a tool to find answers to really difficult questions. We thought we had an answer and it turns out we were almost certainly wrong. But one dead end isn’t failure, that’s how research goes. We learn 10,000 ways how not to do something before we find the correct way. I’m actually excited that this study is making waves for a different reason. I’m hopeful that this will lead to people funding other avenues of research to help find the neurological cause(s) of depression and how to treat it.

Frankly, I’m hopeful that we will stop seeing depression as a single entity from a neurological standpoint and start classifying different types. The better we can understand what’s going on the better we can treat it. This isn’t the end, it’s just a new chapter.


Moncrieff, J., Cooper, R.E., Stockmann, T. et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01661-0


4 responses

  1. The accomplishments of medical science are arguably immense, but sometimes the amount left to do overwhelms me. Barely any high-quality studies on the cause of depression? Really? But I suppose you’re right – admitting that we don’t really understand it is the first step to making any progress. Watching researchers fixate on a simple explanation must have been extra painful for everyone who wasn’t explained by it. Like you were being ignored.

    It does make sense to me that it would be more complicated than a shortage of one hormone. There are many flavors of “feeling down” and many different rational/healthy reasons to feel down, so maybe there are just as many ways for the system to fail and generate misery that doesn’t make sense.

    Last year I was reading up on GBS/CIDP, and it’s kind of a similar story there. They think they know what causes it (the immune system attacking the myelin on peripheral nerves), but they haven’t fully proven that or aren’t sure of the details. The approved treatments only work on a subset of patients. And scientists don’t properly understand why they work when they do. I get why that one’s difficult to study, since it’s a pretty rare disorder to start with. (I don’t think they have that excuse when it comes to studying depression.) Small comfort to anyone who has it! And there are probably an abundance of other strange little disorders like it, that we’re still more or less guessing about.

    Speaking of autoimmune issues, has that stress-related thing that gave you the strange welts been staying quiet? Hope so. I’m glad that with the modafinil you at least aren’t hurting quite as much these days. You really deserved a break.

    Liked by 1 person

    July 23, 2022 at 10:55 pm

    • Yeah it’s kind of scary when you think about it, but depression isn’t a big science topic. We found medications that worked somewhat and just ran with it without verifying that the medications were targeting the thing we thought they were. Basically assumptions built on assumptions. But I’m hoping this will lead to a real shift in the way we research depression and start exploring different mechanisms of action. This could be a good shift to more personalized medicine, but we’ll have to see where the funding goes. Funding really is what drives research, so without it people don’t research topics they may actually be very interested in.

      GBS is a great example. Even though theoretically speaking peripheral nerves are far less complex than the brain we still don’t have a lot of answers, but again funding is (probably) scarce. The most frustrating part is that advancements in treatment/curing diseases like that would almost certainly have downstream effects on our understanding of the nervous system as a whole and how to interact with it. Fibromyalgia is another good example of almost certainly different diseases being lumped together because symptoms are similar. Basically we need to just fund all types of research, but it’s an old song and I don’t know that people are listening.

      Thanks for asking! Arguably better. I had some really good days not that long ago and it felt nice not feeling like I was recovering from a marathon. The modafinil really does help with a lot of that oddly enough, but since we don’t know the mechanism of action for modafinil, it could be placebo or it could be some unknown effect. I haven’t had any real rash outbreaks (more than the normal face stuff which I have medication to treat, so it’s not active) which has been nice. It’s probably why I’ve been getting so much more done. I hope I can convince my psychiatrist to increase my dose though, it’s still way too low IMO.

      How about you? How have you been holding up?

      Liked by 1 person

      July 24, 2022 at 12:40 pm

      • Hey, even if it is some kind of placebo effect, if that’s what helps you then you might as well keep getting it. Improvement is improvement. I hope you do manage to get your dose raised soon.

        “The most frustrating part is that advancements in treatment/curing diseases like that would almost certainly have downstream effects on our understanding of the nervous system as a whole and how to interact with it.” As far as I know from my reading so far, there isn’t even a name for the uniquely horrible sensation of having reduced nerve conduction velocity. But apparently something depends on that and is very sensitive to any deviation in the feedback loops. Other people mostly couldn’t tell there was anything wrong with me, and even during the worst of it, the neurologist described my level of nerve damage as “mild” – he could only measure “small anomalies” in my legs, and nothing in my arms. Meanwhile, some part of my brain was screeching that things were terribly wrong any time I moved. It was like a persistent nausea, except not in my stomach. That probably does say something about how the whole motor control system works, or at least how mine works.

        When it didn’t make me miserable it was kind of fascinating, and I wished from the beginning that I had more resources to study myself. But besides money and access, the other problem is that a lot of the tools are invasive. Just getting my tentative diagnosis confirmed (was it really GBS/CIDP?) would have called for a cerebrospinal fluid sample. The neurologist didn’t think I was in dire enough straits to justify a spinal tap, and I agreed and went home.

        Anyway I’m doing great these days! I can’t say that my symptoms are 100% gone, but they aren’t making me uncomfortable anymore; I basically feel like a normal person again. I just get a hint of the weird “floppy” sensation in my hips and shoulders sometimes, I don’t quite have all my muscle tone back, and a couple months ago I started having random little muscle twitches. Since that’s a late-breaking symptom and everything else is getting better, I hope it’s merely a sign of some badly damaged nerves coming back online and freaking out. So far it’s been harmless, and I much prefer it to the muscle weakness and the flopping/lurching feeling. Thank you for checking on me!

        Liked by 1 person

        July 24, 2022 at 4:12 pm

      • That’s great news! Muscle twitches may be a good sign. In SCI populations when we are using TSS we often see high spasticity or clonus which means we’re reactivating circuits we want (or so we think anyway). I imagine it’s something similar.

        In any case I’m happy to hear you’re doing well! I hope it continues.

        Liked by 1 person

        July 25, 2022 at 10:06 am

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