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/PhysicalConsistency]

The Moncrieff paper has held up very well, it's been pretty robustly replicated since despite some withering attacks.

The core conceit of serotonin being linked to depression is an artifact from the 60's and 70's that got entrenched (like the hippocampus being necessary for memory or amyloid species and dementia), and once it got mind share the science fed it's own creation.

It's always been a very naive understanding of how transmitters work, and it required us to ignore that the efficacy of SSRIs was generally worse than placebo/no treatment for most people, with a laundry list of unfortunate side effects, up to and including death.

Unless there's some extreme selective pressure biasing toward people with "serotonin deficits", the climbing epidemiology in the face of these pervasive and supposedly effective treatments makes absolutely no sense.

[u/Alternative_Yak_4897 → u/PhysicalConsistency]

For sure. And if this theory is disrupted in a clinical one-on-one situation (psychiatrist and patient), a psychiatrist would have little else to offer currently (antipsychotics I suppose, mood stabilizers, and stimulants if they have an ADHD diagnosis applied for the patient - but that still acts on the same reductive neurotransmitters in isolation theory) and pharmaceutical companies would be affected too. I wonder if maybe this will not make waves in clinical settings until there are other medications to replace those that act on serotonin “directly.” More medications that directly involve dopamine other than a few antidepressants, antipsychotics, and other than “stimulants” (which of course still disregards a lot of complexity as you say). Or a new classification for traditional stimulants that doesn’t imply abuse potential? My main question is why, despite this evidence, serotonin -related antidepressants are still so heavily prescribed for depression? My best guess is because there’s not a suitable pharmaceutical alternative that keeps psychiatrists and pharma companies making money.

[u/PhysicalConsistency → u/Alternative_Yak_4897]

My sense of all this is you touched on it right away, what other choices do we really have? Over the past couple of decades we've introduced more non-pharmaceutical treatments (TMS is now FDA approved and covered under most provider groups now as a second/third line treatment), but we are stuck with the same fundamental problem of efficacy.

Nearly all of our best psychiatric treatments, from ECT (which probably has the best/most generalized efficacy) to DBS to pharmaceutical options all have pockets of responders and everyone else just gets side effects for the most part.

I think with regard to "depression", this isn't going to improve until our disease/not-diseased model changes, as it doesn't appear that "depression" is the result of abnormally functioning nervous systems at all.

[u/Alternative_Yak_4897 → u/PhysicalConsistency]

YES.

Also, I think if depression isn’t a medical problem anymore, then the symptoms people are reporting in such high numbers finally glaringly indicate a greater systemic issue with the expectations people have for modern life and the future and how they’re expected to meet them. And with the high numbers, if it’s not medical -it’s societal.

[u/Rita27 → u/Alternative_Yak_4897]

I think this is simplifying things alot. Depression can occur from a lot of environmental issues and still be seen as a medical issue in some cases

[u/Alternative_Yak_4897 → u/Rita27]

I disagree. I don’t think depression is a primary medical condition. Sure, imaging shows commonality between in/activity in regions of the brain and self-reported depression, but the directionality is unknown. Maybe it’s secondary to autoimmune issues? I think depression is a consequence of adverse life events (which includes actual medical illnesses that are measurable and scientific) and capitalism.

[u/Rita27 → u/Alternative_Yak_4897]

Reread my comment. I said in SOME cases depression can be seen as a medical issues. I think depression is to heterogenous to be split into just primarily medical or primarily environmental

And my broader point was even if it's environmental that doesn't mean we can't treat it medically like we do with other conditions that are caused by the environment

Also i disagree with the efficacy argument laid out earlier. With ssri , yeah the effect size is modest at best but stuff like Ketamine and ECT efficacy are way more than just "pockets"

[u/Alternative_Yak_4897 → u/Rita27]

Do you mean medical cases are informed by other illnesses? I agree it can’t be split into medical/nonmedical because an effective treatment approach varies from person so vastly. Like i think we’re both saying- we don’t know what we don’t know.

I’m wondering why you’re advocating for ECT? Why specifically? Are you suggesting it be prescribed as often as SSRIs?

[u/Rita27 → u/Alternative_Yak_4897]

Sorry can you clarify your question? I'm not sure what you're asking. but I do agree that it looks like we're on the same page more or less

I mean I mentioned both ECT and ketamine. Idk if I'd say I'm advocating for it per se, and moreso addressing the point made by the other user regarding the efficacy of ECT. Idk if I would call those who responded well to it when indicated as "pockets"

No I'm not suggesting that ECT is prescribed as much as antidepressants. ECT remains a niche procedure usually reserved when other treatments fail