The serotonin theory of depression: a systematic review of the evidence (2022)

Important to note that the serotonin theory of depression doesn't have to be strictly true for SSRIs to be effective. People who having passing familiarity with neuroscience often assume that psychiatric medications work by correcting deficiencies, but this isn't true. It's also not accurate to say that SSRIs "give you more serotonin" or any of the other variations on that theme.

Neurotransmitters aren't simple levels in the brain that go up and down, despite how much podcasters and fitness influencers talk about them like that. Neurotransmitter dynamics are complex and the long-term adaptations after taking medications like an SSRI can't be simply described in terms of "levels" going up and down. There are changes in frequency, duration, and movement of Serotonin across synapses that are much more complex. There are also adaptations to the receptors, including auto-receptors which modulate release of neurotransmitters (side note: some newer antidepressants also directly target those autoreceptors with possibly slight improvements in side effect profile).

So keep that in mind when reading anything about the serotonin theory of depression. This is often brought up as a strawman argument to attack SSRIs, but we've known for decades that the serotonin theory of depression never fully explained the situation. We've also known that some conditions like anxiety disorders are associated with increased serotonin activity in parts of the brain, which SSRIs can normalize.

A fairly surprising fact revealing how little we understand the efficiency of SSRIs is that the serotonin level rises pretty quickly once you have started taking an SSRI.

Still, there is an unexplained cascade of reactions that takes weeks before patients notice any improvement.

As much as I respect proof-based medicine, the very fact that scientists can't explain how all this works made me want to stop my treatment and just do more weightlifting and running.

>how little we understand the efficiency of SSRIs

A drug that is taken by millions of people, if your take is that we understand it too little, either you are deep enough in the subject to make some interest questions, or you are missing the forest for the trees.

I'm not sure how useful it is to keep investigating exactly how it works on a chemical level, yeah for sure some people should look into it, but in the same way that some one should do 1600m in the regional competition of Minnesotta, as a niche.

You can observe the effects of the medication on people, done.

I remember seeing a video on a cannabis researcher explaining that they didn't find any difference between the indica and sativa strains for example, and she talked about chemical properties. Just get 10 people to smoke one or the other and you are done.

There is such a thing as overintellectualizing, and FUTON bias isn't a particularly impressive way to do it.

> "I'm not sure how useful it is to keep investigating exactly how it works on a chemical level"

It has the potential to be incredibly useful.

Not because there's a benefit to being able to tell patients "this is the technical explanation of how the SSRI we're giving you will help", but because we currently don't have a perfect treatment for depression, and understanding how existing imperfect (but useful) treatments actually work might lead to either creating better SSRIs that are more effective, or to creating non-SSRI treatments that we haven't yet thought of.