“No convincing evidence” that depression is caused by low serotonin levels

So...why do SSRI users self-report efficacy?

My guess, without digging into the study itself since I'm on mobile, is that there is no singular cause for depression. Rather, depression is simply a symptom of a wide range of causes, with one possible cause being low serotonin (or a reduced sensitivity to it). Or even, low serotonin is a symptom of the depression.

Not all patients with depression find relief from SSRIs, or medications in general, but some certainly do.

This is completely unsurprising and indicative of how limited our understanding of the brain is.

It reminds me of Pfizer's work on gabapentin. A professor from Northwestern was working on GABA antagonists (by modifying GABA itself) and eventually came up with the drug. It was hailed as a great example of "structure-based drug design".

The drug was approved by the FDA and efficacious for a number of issues like neuropathic pain. The submission documents from Pfizer had all this data on the binding efficiency of the drug to GABA receptors.

Except it didn't work through the GABA receptor at all.

After approval, more research was done and they said it worked through glutamate channels. Then more work was done and it seems most of its effect is through calcium channels.

Yes, but according to Irving Kirsch, the benefit of anti-depressants above placebo is very small for anyone who isn't severely depressed, and the observed small effects can plausibly be explained by patients unblinding themselves (due to the presence of other side effects in the treatment group), or by things like publication bias.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172306/