The mechanisms of depression

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.

Source:

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