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

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.

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.

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/

> SSRIs aren’t shown to be much better than placebo

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

> 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

> 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.