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

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169 points flaxxen | 1 comments | 27 Feb 25 18:27 UTC | HN request time: 0s | source
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Aurornis ◴[28 Feb 25 19:47 UTC] No.43209537[source]▶
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.

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aeturnum ◴[28 Feb 25 19:59 UTC] No.43209670[source]▶
Exactly this - SSRI's efficacy was established based on improvements in reports from depressed people and we formed a theory about the mechanism based on the interactions we understood. As we try to prove that theory out it turns out our theories don't hold - but people who are depressed still improve when on SSRIs! So we're still working on the mechanism (which we always knew was incomplete at best) but this work isn't about the underlying efficacy of the drugs on the condition. It's about the nerdy explanation for why SSRIs work.
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arcticbull ◴[28 Feb 25 20:33 UTC] No.43210180[source]▶
SSRIs aren’t shown to be much better than placebo and are shown to be about as effective as therapy — which is actually durable.

There’s also rates of sexual side effects in excess of 70% [1] and they cause weight gain which is separately associated with depression.

In fact industry data shows a smaller gap between SSRIs and placebo than FDA data. See Figure 1. [2]

The problem with SSRIs is that serotonin receptors are all over the body including in the gonads and they play a large role in appetite regulation.

They do something but it’s not nearly what people assume.

[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC6007725/

[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC4592645/

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Blackthorn ◴[28 Feb 25 21:37 UTC] No.43211601[source]▶
> SSRIs aren’t shown to be much better than placebo

Or in other words: it's better than placebo.

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crdrost ◴[28 Feb 25 22:08 UTC] No.43212196[source]▶
> Finally, Jauhar et al. argue that serotonin must be involved in depression because drugs which target the serotonin system are effective and other authors also argue that antidepressants ‘work’. However, whether antidepressants produce a genuine and useful pharmacological effect that is independent of the placebo effect, has not been established. Antidepressants show marginal differences from placebo, which do not fulfil criteria for clinical relevance, and may represent amplified placebo effects due to unblinding [31,32,33]. It is hard to reconcile even the most generous appraisal of their efficacy with the vast numbers of people now taking them. Contrary to Bartova et al’s claims, the idea that antidepressants reduce suicide has not been established, and evidence from randomised trials suggests they increase the risk of suicidality in some age groups [34, 35].

-- Monicreff et al. (2023), https://www.nature.com/articles/s41380-023-02094-z

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alpaca128 ◴[28 Feb 25 22:42 UTC] No.43212691[source]▶
> whether antidepressants produce a genuine and useful pharmacological effect that is independent of the placebo effect, has not been established

As someone who has experience with antidepressants that goes beyond looking at numbers I can assure you that effect has been established very clearly. And it has nothing to do with placebo, only the second medication was the one that worked - it did more in three days than the first one after months on the highest dose.

These studies sound to me like the attempts to find out whether life exists on a planet by analyzing some light spectrum through a telescope. I am sure they are useful but they seem a bit blind to what's actually going on in real life.

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1. crdrost ◴[01 Mar 25 03:18 UTC] No.43215400{3}[source]▶
So that was a quote from a piece from the same author as the original article.

I'm trained in physics, not medicine, so I am somewhat reluctant to give my own take. I have not been on SSRIs myself but I have been the responsible one for making sure that folks take them. But I would note these points about what I see in the general discussion:

• Nobody is saying the SSRIs aren't psychoactive compounds that could maybe be helpful for at least short-term intervention. Everyone agrees on at least those two things. So, nobody is telling you that you didn't feel something helpful with that second one.

• The psychiatric practice is indeed to “shop around” not just different drugs, but different generics of the same drug. To my mind this basically proves the point: if you had had a serotonin problem, the first SSRI would have fixed it and the only question would be “can you tolerate the side effects?”. So actually what's fixing the problem is a side effect of the SSRI, it is not the main effect of boosting serotonin, but it's the other ways in which these particular drugs happen to be psychoactive.

• Your first person anecdotal experience obviously is not a disproof of a placebo effect and it cannot be—this is I think you applying a popular misconception that placebo effects “don't feel real” or “don't last” or “aren't real medicine” or whatever, but they do, and they can, and they are. In these tests there is never a control that didn't get either the medicine or the placebo, which I actually find kinda frustrating—so “placebo” also means “control group.” It's just a measure of all the things that you didn't have control over. But it's called that because they give the control group a placebo. But like I don't have control over air quality, air quality can affect sleep quality, sleep quality can affect depression, if I start my experiment during a week of bad air quality and it gets better for the rest of the experiment, that generates both a “placebo” signal and a “test” signal, even though that's not the placebo effect. If you're peeking in as a physicist you've got to remember that the body heals the vast majority of our medical problems on its own, and that psychiatric problems are even moreso because “I made a new best friend at the XYZ study, now we go for walks every day together and complain about all the things that are making us more depressed this week” can fix a psychiatric problem much more easily than, say, putting cancer in remission. So like the body heals itself, the brain heals itself, the brain also has influence over physical context (“I am going to eat some broccoli and go on a walk today”), the brain also has influence over psychosocial context (“I’m gonna go no-contact with my abusive parent,” vs “I will get stuck curled in a ball in bed saying ‘I’m useless, I’m useless’ until my physics-major housemate has to remind me to get up and drink a sip of water and swallow my medicine.”) There's just so many ways the contexts are plastic, and they are all valid medicine in that context, going no-contact with an abusive parent can absolutely be therapeutic. So, placebo means control, it doesn't mean that the healing wasn't real, it just means that the healing was out of the control of the experiment, which was only looking at this particular drug.

• Finally, because these tests are done one drug at a time, this fact that they don't beat the placebo group with the test group, comes out even more nuanced. Remember that you are not being healed by the main effect of an SSRI but one of its side-effects. The question is, is that repeatable for others with depression or did it only work for your depression because it happened to take the edge off of this or that subsystem in your brain’s feedback loops, but that subsystem isn't critical to someone else's depression? Hypothesis: the failure of SSRIs to beat placebos in these tests, means that biologically there are 20+ different “depressions” and when you are “depressed” we don't know which one you have (or maybe you have even more than one!), and each of these drugs is only able to make an impact on say five of those different depressions, and whether it is worth the side effects depends on even more concerns. Meanwhile everyone in the control group gets to cure 4 of the depressions at random, say. Does your second medicine beat the placebo? Well, not for everybody. Not even for the vast majority. But for people in your particular circumstance it does. But we don't have the ability to isolate that circumstance.

In conclusion, if you are looking at medicine as a physicist, everything is f*¢#ed and it's so much nicer to play with my quantum dots and lasers and liquid nitrogen.