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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: 0.21s | 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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1. IX-103 ◴[28 Feb 25 22:29 UTC] No.43212539[source]▶
If you ask any practicing psychiatrist, you'll see that they are aware of the problems with SSRIs. They tell their patients that they may need to try several drinks until they find one right for them.

The way you presented those statistics is very misleading. The 70% number for sexual side effects you quoted was actually for patients that stopped taking at last once drug for that reason. Typically patients will have to try 2-3 drugs to find something that works for them and may need to transition to a new drug when the old one is no longer effective. So it's not like those patients are facing those side effects on an ongoing basis. It's just during the initial period when they are adjusting things.

I suspect that the reason why SSRIs perform so poorly in the studies is that the amount of variation in these receptor targets is high, so some drugs actually are effectively placebos to a large fraction of people. But for other individuals they are a miracle. And if you multiply that by the number of different drugs, you can almost always find one of them that helps each patient.

This goes into your assertion about "serotonin receptors are all over the body". That's something doctors and medical researchers have known for a long time. That's why the SSRIs are tailored to the specific variants of the serotonin receptors present in the organs they want to influence. That doesn't mean they have no effect on the receptors in other organs, but that the effect is minimized to the extent possible. But I suspect that one limitation in how tightly we're able to target the right receptors has to do with individual variation - make it specific enough that it doesn't affect other organs then it doesn't work for anybody with the slightest variation in target receptor shape.

But I agree that the role serotonin plays in depression is poorly understood. But I don't agree with the implication of your post that we should stop using them. They are often helpful even in cases where therapy is insufficient, and improve outcomes in conjunction with therapy. They are too useful a tool to discard, even with their issues.