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.

Yep, all very good points. Neuropsychopharmacology is extremely and recursively complicated. It's turtles all the way down. Just take one component in all this, the receptor. One might want to think of a receptor as just a switch triggered by a chemical. But autoreceptors are a thing, as you mention. Receptors do different things in different areas of the brain. Receptors form complexes with eachother(e.g 5-HT-2a and D2), and we have essentially no idea why? Receptors have all sorts of different modes of interaction both with ligands and cell internals. Agonism, partial agonism, antagonism, inverse agonist, positive/negative allosteric modulation. The GABA-A receptor is not really one receptor, it's more like a family of receptors made up of a varying constellation of subunit proteins. Different constellations appear in different parts of the brain, and have different allosteric binding sites, which is why benzos vary widely in qualitative effects despite all being "GABA-A PAMs". NMDA receptors don't just bind to glutamate, but also glycine, and magnesium needs to be around? And NMDA triggers an intracellular cascade that regulates membrane expression of AMPA receptors. This is thought to be involved in memory. Cannabinoid receptors are expressed presynaptically carry signals in reverse, so that's weird. And there are 5 identified cannabinoid receptors. We only sort of understand what 2 of them even do. The other 3 are still quite mysterious(last time I checked). Most of the well studied neurotransmitters have not one, but many different receptors they interact with. 5-6 dopamine receptors, I can't even remember all the serotonin receptors, etc. Many of them are still poorly understood.

And of course, neurotransmitter systems talk to eachother. Serotonin so much so that it's also been called a neuromodulator. Because it very often regulates release of other neurotransmitters(including itself).

It's a field that, the more I dig into it, the more confused I get, honestly.

So when I see someone say herp derp, serotonin hypothesis is false, therefore SSRIs are ineffective, the only conclusion I can make is they haven't even tried to dig into it.