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bannedPosts t1_j8tngcw wrote

Receptor binding and conformational dynamics is highly complex. Just because two chemicals bind at the same site, doesn't mean they elicit similar outcomes. Rarely do chemicals bind to only one site either.

The serotonin hypothesis of depression will just not die. 2022 - "The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations."


rjmsci OP t1_j8tpods wrote

I think quoting the Moncrieff paper is a mistake here - that's an article with an agenda. Depression is not caused by lowered serotonin activity, sure, but compounds that primarily modulate the serotonin system do relieve it. It's up to the field to unravel the mechanisms behind this. Do these intracellular 5ht2as kick off pathways that surface receptors don't? How do different serotonin agonists affect these receptors? This is exactly the kind of research the field needs to answer these questions.


The-Crawling-Chaos t1_j8u9m24 wrote

> Depression is not caused by lowered serotonin activity, sure, but compounds that primarily modulate the serotonin system do relieve it.

Which isn’t surprising when their response rate is only ~10% higher than the placebo- controlled response rates for depression of ~40% on average.

source 1 Source 2 Source 3 (another Moncrieff)


peer-reviewed-myopia t1_j8wac9x wrote

I think it's a mistake to say compounds that primarily modulate the serotonin system relieve depression.

Considering the delayed 'time of effect' of the therapeutic actions of compounds targeting the serotonin system, it's clear the adaptive structural / functional changes are not specific to serotonergic signaling — be it at the synaptic, or intracellular level.

For example, underlying these changes in plasticity are interactions with the BDNF system, as pretty much all effective antidepressant therapies lead to increases in levels of BDNF mRNA.

There are plenty of other systems at play, and they interact via a variety of feedback mechanisms to regulate the circuits involved in affective behaviors.


nickyfrags69 t1_j8x8ysr wrote

>but compounds that primarily modulate the serotonin system do relieve it

That's not necessarily accurate though. First off, Ketamine has a much higher success rate, suggesting at the bare minimum that other mechanisms can relieve depression without touching serotonin receptors. Second, most of the benefit of SSRIs seem to be indirect/downstream, which is why they take so long to kick in.


km89 t1_j8ukh6r wrote

Coming from a place of total ignorance here, is there any explanation for why SSRIs work so well, assuming serotonin isn't correlated with depression?


AeonDisc t1_j8v0vnw wrote

Isn't the success rate of treating depression with SSRI's actually rather low?


69tank69 t1_j8uqnie wrote

We don’t fully know. But some research has gone into looking at serotonin boosting Neuro plasticity with conventional anti depressants triggering the 5HT1A. Unfortunately checking mechanisms deep in the brain are very difficult to do but if your interested in that side I would consider reading some articles on the Neuro plasticity hypothesis of depression


bannedPosts t1_j8ytvrk wrote

There's no explanation - aside from wishful thinking - SSRIs do not work any better than placebo. In fact, the most reliable predictor of efficacy is believing they will work. If your doc can sell it, it might work. Sounds like religion to me. If, and I say if, SSRIs worked as advertises they would work in a few days not months / years. No other class of drugs enjoys more apologists than SSRIs.


km89 t1_j8yvud9 wrote

I would very much like to see data on this.


ERSTF t1_j90l9bf wrote

I did not know this. Would love to see the data. As an ignorant myself. What is best for treating depression?