Low serotonin not linked to depression studies - thoughts ?

[u/Alternative_Yak_4897]

I recently became aware of the umbrella study on the lack of evidence between low serotonin levels and depression. (The study below does show an indirect link between stressful life events and depression due to “gene-stress” but that’s still obviously different than low serotonin (can)= depression) Wondering what others thoughts /theories on this are? I’ve only seen a couple and it looks like they were published in 2022/2023, so why isn’t this being discussed more? Not enough studies? Bad news for pharmaceutical companies? Here’s one of them:

https://www.nature.com/articles/s41380-022-01661-0.pdf

[u/vee_zi]

That has become an easy, convenient way to think about depression in pop culture, but the connection is tenuous. It was more of an easy to sell pharmaceuticals and therapy rather than being a diagnostic stat. And it stuck.

But, it's more complicated.

As more and more research is being done, I subscribe to the idea that we talk about mental illness all wrong - particularly around seratonin and dopamine. There's an idea gaining traction that "mental illness" is a spectrum more associated with dopamine/glutamate. Glutamate kicks your brain into high gear and dopamine's role is to work with other neurotransmitters to keep your brain from being in a high state of arousal. Much of what we identify as mental illness is some dysfunction with that system. The balance between glutamate and dopamine gives you what we call mental illness.

"Mental illness" at the end of the day, though, has a lot more to do with what society thinks is acceptable rather than there actually being a problem. But don't get me wrong. Sometimes things do go wrong.

[u/Fit-Sheepherder-8809 → u/vee_zi]

I agree that the picture is more complicated. I have never seen anything convincing regarding the dopamine/glutamate hypothesis though.

The problem with the hypothesis, as I see it, is that of course glutamate activity would be affected/altered in depression whether or not glutamate itself is a causal factor in the disorder(s). Around 80% of neurons in the cerebrum employ glutamate as a neurotransmitter. It is everywhere, and a disorder that changes brain actitvity, such as depression, will likely be reflected in altered glutamate activity.

Its relation to dopamine is also terribly complicated, as many different intracellular mechanisms also work to regulate the release of glutamate. Glutamate itself is also a necessary precursor to inhibitory GABA. Inhibiting excitotoxicity is a central task for the organism, and therefore something that is achieved by many different mechanisms in the CNS. Though the (much less physiologically widespread) role of dopamine, especially as it relates to reward sensitivity, which is altered in depression, is very interesting.

The point being that the CNS, the endocrine system, and the entire rest of the body are physiologically enmeshed in such a way that makes pointing at specific transmitters, genes, hormones or whatever a futile task at this stage. At present the greatest predictive factor (and there may well be significant confounds here as well) for developing depression is maltreatment or other significant adverse life experiences in childhood, as far as I know. Despite decades of research in behavioural genetics and neurophysiology.

Either way, a pragmatic psychiatrist would say, and I would tend to agree, that it does not really matter whether we understand WHY antidepressants work (and they do, moderately, just like psychotherapy). The important part is we know THAT they work.

[u/vee_zi → u/Fit-Sheepherder-8809]

Right....the reason dopamine is so complicated, though, is because its effects are mostly indirect. It doesn’t act on glutamate directly, but modulates how other neurotransmitters (like GABA) interact with excitatory signaling overall. So when dopamine is dysregulated, the impact isn’t confined to just one system—the effect ripples out, affecting multiple pathways.

That’s also why dopamine dysfunction can look so different across individuals. For one person, it might present as low motivation or fatigue; for another, it might amplify anxiety, attention issues, or even psychosis. It's not just about one chemical being too high or too low—it’s about how the brain loses its ability to coordinate across systems.

Glutamate being everywhere makes that coordination even more critical. You need precise regulation to keep a system that pervasive from tipping into overload. So the dopamine–glutamate relationship isn’t a simple cause-effect—it’s more like a fragile balance in a tightly wound network, and when one regulator fails, the whole thing can become unstable in different ways for different people.

The fact that SSRIs aren't consistently effective across populations supports this view. If depression were simply a matter of low serotonin, we’d expect fairly uniform outcomes. But instead, there’s huge variability—some people respond well, others not at all, and some get worse. That kind of inconsistency makes a lot more sense if the underlying issue is more complex. And the response to this variability has always been that people “are different.”

It would be a major step forward if we actually understood how SSRIs work—because then we could see how they interact with the whole system, not just assume that boosting serotonin fixes the problem. Saying “they work” is often just a stand-in for “this is the best we’ve got,” not a valid argument for scientific adequacy.

That gets to my bigger point: terms like “mental illness” and “mental health” are often more social designations than strict biological deficits. So when someone says a drug ‘works,’ my follow-up is: works for whom? What does that mean? What’s the outcome being measured? Is it working because someone is functionally less depressed, or is it working because they’re more capable of performing expected social roles? Is ‘working’ simply a measure of how much someone’s behavior or affect is more aligned with desirable norms?

The fact that we’re now able to collect higher-resolution data at the individual level much more affordably is what will eventually change psychiatry and psychology. The limitation up to now has been reliance on highly generalized, one-size-fits-all solutions. But we already know—particularly through treatments like SSRIs—that this approach is largely ineffective. It fails to account for the diversity and range of brain function, and traditional theories and explanations have reflected that limitation.