Some have found flaws with Kirsh's study and there is still an ongoing debate about effectiveness. [1] I am not a fan of prescribing so many people a drug that we don't know how it even works for what is often just a small improvement, but I don't think its accurate to say they are useless.
[1] https://academic.oup.com/ijnp/article/14/3/405/906146#156821...
I think they don't work because Depression, like Alzheimer's, is poorly defined.
From a population genetics perspective we can find clear genetic signals for other psychiatric disorders such as Schizophrenia, ADHD, etc. But Depression is notoriously difficult to identify any genetic signal for. Its my opinion that this is because Depression is more often a symptom of another psychiatric disorder and only rarely is the root cause just Depression itself.
Many folks with ADHD, Bipolar, or other "mild" disorders go undiagnosed and get the Depression label instead and this muddies the waters.
I think I read that amyloid may be a body immune reaction to infection which is why targeting that rather than the infection is ineffective. (not expert on this but the article is interesting).
It's easy to look at studies and say "this shit doesn't work" (despite there being plenty of studies that show they're clearly effective and they're one of the best treatments we have). But when you talk to people taking it, clearly there are way too many that benefit from them to just say we need to stop prescribing them. That's just deciding due to your own biases that countless people need to suffer unnecessarily. Why? Why would you want to do this to people? Or do you not actually care about the suffering or wellbeing of the people affected and you just have this vague idea of "SSRIs bad"?
I spent a lot of time reading studies before going on SSRIs to decide whether it was worth it. The literature unambiguously said that SSRIs are absolutely a valid form of treatment that can help (even though it won't help everybody). Who are you to say they're horseshit?
How about SSRIs, for which much of the research does not provide supporting evidence? E.g. there's a 2022 meta-study by Moncrieff et al that shows there's no consistent evidence tying serotonin to depression. An earlier 2008 placebo-controlled study by Kirsch et al shows that SSRIs are barely any better than placebo.
IOW, SSRIs are useless horseshit for the vast majority of people (especially in the absence of e.g. CBT) and the theory behind them is not supported by evidence. Why are they still prescribed?